Methods for the stereoselective synthesis of substituted piperidines

ABSTRACT

One aspect of the present invention relates to methods of synthesizing substituted piperidines. A second aspect of the present invention relates to stereoselective methods of synthesizing substituted piperidines. The methods of the present invention will find use in the synthesis of compounds useful for treatment of numerous ailments, conditions and diseases that afflict mammals, including but not limited to addiction and pain. An additional aspect of the present invention relates to the synthesis of combinatorial libraries of the substituted piperidines using the methods of the present invention. An additional aspect of the present invention relates to enantiomerically substituted pyrrolidines, piperidines, and azepines.

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S.Provisional Patent Applications Ser. No. 60/251,209, filed Dec. 4, 2000;and 60/275,600, filed Mar. 13, 2001.

BACKGROUND OF THE INVENTION

[0002] Pain is an unpleasant sensation varying in severity in a localpart of the body or several parts of the body resulting from injury,disease, or emotional disorder. Pain can be classified according to itsduration. Acute pain, which lasts less than one month, usually has areadily identifiable cause and signals tissue damage. In addition, acutepain syndromes can be episodic, for example recurrent discomfort fromarthritis. Chronic pain can be defined as pain that persists more thanone month beyond the usual course of an acute illness or injury, or painthat recurs at intervals over months or years, or pain that isassociated with a chronic pathologic process. In contrast to acute pain,chronic pain loses its adaptive biologic function. Depression is common,and abnormal illness behavior often compounds the patient's impairment.

[0003] Millions of people suffer from chronic or intractable pain.Persistent pain varies in etiology and presentation. In some cases,symptoms and signs may be evident within a few weeks to a few monthsafter the occurrence of an injury or the onset of disease, e.g. canceror AIDS. Like many illnesses that at one time were not well understood,pain and its many manifestations may be poorly treated and seriouslyunderestimated. Inappropriately treated pain seriously compromises thepatient's quality of life, causing emotional suffering and increasingthe risk of lost livelihood and disrupted social integration. Severechronic pain affects both the pediatric and adult population, and oftenleads to mood disorders, including depression and, in rare cases,suicide.

[0004] In the last several years, health policy-makers, healthprofessionals, regulators, and the public have become increasinglyinterested in the provision of better pain therapies. This interest isevidenced, in part, by the U.S. Department of Health and Human Services'dissemination of Clinical Practice Guidelines for the management ofacute pain and cancer pain. There is currently no nationally acceptedconsensus for the treatment of chronic pain not due to cancer, yet theeconomic and social costs of chronic pain are substantial, withestimates ranging in the tens of billions of dollars annually.

[0005] Three general classes of drugs are currently available for painmanagement, nonsteriodal anti-inflammatories, opioidids, and adjuvantanalgesics. The nonsteriodal anti-inflammatories class includes drugssuch as aspirin, ibuprofen, diclofenac, acetaminophen, celecoxib, androfecoxib. The opioid class includes morphine, oxycodone, fentanyl, andpentazocine. Adjuvant analgesics include various antidepressants,anticonvulsants, neuroleptics, and corticosteroids.

[0006] Opioids are the major class of analgesics used in the managementof moderate to severe pain because of their effectiveness, ease oftitration, and favorable risk-to-benefit ratio. Opioids produceanalgesia by binding to specific receptors both within and outside theCNS. Opioid analgesics are classified as full agonists, partialagonists, or mixed agonist-antagonists, depending on the receptors towhich they bind and their intrinsic activities at each receptor.

[0007] Three subclasses of opioid receptor have been identified inhumans, namely the δ-, κ-, and μ-opioid receptors. Analgesia is thoughtto involve activation of μand/or θ receptors. Notwithstanding their lowselectivity for μ over θ receptors, it is likely that morphine andmorphine-like opioid agonists produce analgesia primarily throughinteraction with μ receptors; selective agonists of θ receptors inhumans produce analgesia, because rather than the euphoria associatedwith morphine and congeners, these compounds often produce dysphoria andpsychotomimetic effects. The consequences of activating δ receptors inhumans remain unclear.

[0008] Although opioids can be very effective in pain management, theydo cause several side effects, such as respiratory depression,constipation, physical dependence, tolerance, and withdrawal. Theseunwanted effects can severely limit their use.

[0009] Opioids are known to produce respiratory depression that isproportional to their analgesia. This respiratory depression can be lifethreatening. This results in a narrow range between the effective doseand a dose that produces respiratory depression. Because of this narrowtherapeutic index, patients receiving opioid therapy must be closelymonitored for signs of respiratory failure.

[0010] Opioids can also cause constipation in individuals receivingthem. This side effect can be severe and may require prolongedhospitalization, or even surgical intervention.

[0011] Commonly used full agonists include morphine, hydromorphone,meperidine, methadone, levorphanol, and fentanyl. These opioids areclassified as full agonists because there is not a ceiling to theiranalgesic efficacy, nor will they reverse or antagonize the effects ofother opioids within this class when given simultaneously. Side effectsinclude respiratory depression, constipation, nausea, urinary retention,confusion, and sedation. Morphine is the most commonly used opioid formoderate to severe pain because of its availability in a wide variety ofdosage forms, its well-characterized pharmacokinetics andpharmacodynamics, and its relatively low cost. Meperidine may be usefulfor brief courses (e.g., a few days) to treat acute pain and to managerigors (shivering) induced by medication, but it generally should beavoided in patients with cancer because of its short duration of action(2.5 to 3.5 hours) and its toxic metabolite, normeperidine. Thismetabolite accumulates, particularly when renal function is impaired,and causes CNS stimulation, which may lead to dysphoria, agitation, andseizures; meperidine, therefore, should not be used if continued opioiduse is anticipated.

[0012] The development of physical dependence with repeated use is acharacteristic feature of the opioid drugs, and the possibility ofdeveloping drug dependence is one of the major limitations of theirclinical use. Almost all opioid users rapidly develop drug dependencywhich can lead to apathy, weight loss, loss of sex drive, anxiety,insomnia, and drug cravings. Although physical dependence is common,addiction and abuse are not common in pain patients who are treatedappropriately with opioid drugs.

[0013] Historically, the development of analgesic tolerance was believedto limit the ability to use opioids efficaciously on a long-term basisfor pain management. Tolerance, or decreasing pain relief with the samedosage over time, has not proven to be a prevalent limitation tolong-term opioid use. Experience with treating cancer pain has shownthat what initially appears to be tolerance is usually progression ofthe disease. Furthermore, for most opioids, there does not appear to bean arbitrary upper dosage limit, as was once thought.

[0014] Cessation of opioid administration may result in a withdrawalsyndrome. Symptoms of withdrawal are often the opposite of the effectsachieved by the drug; withdrawal from morphine, however, results incomplex symptoms that may seem unrelated to its effects.Misunderstanding of addiction and mislabeling of patients as addictsresult in unnecessary withholding of opioid medications. Addiction is acompulsive disorder in which an individual becomes preoccupied withobtaining and using a substance, the continued use of which results in adecreased quality of life. Studies indicate that the de novo developmentof addiction is low when opioids are used for the relief of pain.Furthermore, even opioid addicts can benefit from the carefullysupervised, judicious use of opioids for the treatment of pain due tocancer, surgery, or recurrent painful illnesses such as sickle celldisease.

[0015] The known opioids have been very effective in pain management.However, they have restricted use because of several potentially severeside effects. Therefore, there is a current need for pharmaceuticalagents that retain the analgesic properties of the known opioid, butthat have reduced side effect profiles.

[0016] Additionally, dopamine, norepinephrine and serotonin aremammalian monoamine neurotransmitters that play important roles in awide variety of physiological processes. Therefore, compounds thatselectively modulate the activity of these three neurotransmitters,either individually, in pairs, or as a group, promise to serve as agentseffective in the treatment of a wide range of maladies, conditions anddiseases that afflict mammals due to atypical activities of theseneurotransmitters. Interestingly, a significant portion of the knowncompounds that modulate the activity of these three neurotransmitters,either individually, in pairs, or as a group, comprise a substitutedpiperidine moiety.

[0017] Dopamine plays a major role in addiction. Many of the conceptsthat apply to dopamine apply to other neurotransmitters as well. As achemical messenger, dopamine is similar to adrenaline. Dopamine affectsbrain processes that control movement, emotional response, and abilityto experience pleasure and pain. Regulation of dopamine plays a crucialrole in our mental and physical health. Neurons containing theneurotransmitter dopamine are clustered in the midbrain in an areacalled the substantia nigra. In Parkinson's disease, thedopamine-transmitting neurons in this area die. As a result, the brainsof people with Parkinson's disease contain almost no dopamine. To helprelieve their symptoms, these patients are given L-DOPA, a drug that canbe converted in the brain to dopamine.

[0018] Norepinephrine, also called noradrenaline, is a neurotransmitterthat also acts as a hormone. As a neurotransmitter, norepinephrine helpsto regulate arousal, dreaming, and moods. As a hormone, it acts toincrease blood pressure, constrict blood vessels and increase heartrate-responses that occur when we feel stress.

[0019] Serotonin (5-hydroxytryptamine 5-HT) is widely distributed inanimals and plants, occurring in vertebrates, fruits, nuts, and venoms.A number of congeners of serotonin are also found in nature and havebeen shown to possess a variety of peripheral and central nervous systemactivities. Serotonin may be obtained from a variety of dietary sources;however, endogenous 5-HT is synthesized in situ from tryptophan throughthe actions of the enzymes tryptophan hydroxylase and aromatic L-aminoacid decarboxylase. Both dietary and endogenous 5-HT are rapidlymetabolized and inactivated by monoamine oxidase and aldehydedehydrogenase to the major metabolite, 5-hydroxyindoleacetic acid(5-HIAA).

[0020] Serotonin is implicated in the etiology or treatment of variousdisorders, particularly those of the central nervous system, includinganxiety, depression, obsessive-compulsive disorder, schizophrenia,stroke, obesity, pain, hypertension, vascular disorders, migraine, andnausea. Recently, understanding of the role of 5-HT in these and otherdisorders has advanced rapidly due to increasing understanding of thephysiological role of various serotonin receptor subtypes.

[0021] Although various methods have been reported for laboratorysynthesis of piperidines, the vast majority of these methods are notsuitable for a commercial-scale process. Moreover, there are no reliablestereoselective methods for the controled asymmetric synthesis ofsubstituted piperidines. The disadvantages of the traditional syntheticmethods include modest overall yields and poor stereoselectivities.Moreover, small amounts of by-products, such as undesired stereoisomers,often accumulate during the synthetic protocol, making completepurification of the final product difficult.

SUMMARY OF THE INVENTION

[0022] One aspect of the present invention relates to methods ofsynthesizing substituted piperidines. A second aspect of the presentinvention relates to stereoselective methods of synthesizing substitutedpiperidines. The methods of the present invention will find use in thesynthesis of compounds useful for treatment of numerous ailments,conditions and diseases that afflict mammals, including but not limitedto addiction and pain. An additional aspect of the present inventionrelates to the synthesis of combinatorial libraries of the substitutedpiperidines using the methods of the present invention. An additionalaspect of the present invention relates to enantiomerically substitutedpyrrolidines, piperidines, and azepines.

BRIEF DESCRIPTION OF THE FIGURES

[0023]FIG. 1 depicts certain structural classes of substitutedpiperidines that can be prepared according to the methods of the presentinvention.

[0024]FIG. 2 depicts a proposed asymmetric synthesis of a 3-substitutedpiperidine.

[0025]FIG. 3 depicts a proposed asymmetric synthesis of a 3-substitutedpiperidine.

[0026]FIG. 4 depicts a proposed asymmetric synthesis of a 3-substitutedpiperidine.

[0027]FIG. 5 depicts a proposed asymmetric synthesis of a 3-substitutedpiperidine.

[0028]FIG. 6 depicts a proposed asymmetric synthesis of a 3-substitutedpiperidine.

[0029]FIG. 7 depicts schematically synthetic routes to compounds 37 and2.

[0030]FIG. 8 depicts schematically synthetic routes to compounds 35 and36.

[0031]FIG. 9 depicts schematically a synthetic route to compounds 9 and12.

[0032]FIG. 10 depicts schematically a synthetic route to compounds 17,19, 33, and 34.

[0033]FIG. 11 depicts an HPLC chromatogram of a mixture of stereoisomers15, 16, 27, and 28.

[0034]FIG. 12 depicts the HPLC chromatogram of purified stereoisomer 15(R,S).

[0035]FIG. 13 depicts the HPLC chromatograms of purified stereoisomer 27(S,S).

[0036]FIG. 14 depicts the HPLC chromatograms of purified stereoisomer 16(R,R).

[0037]FIG. 15 depicts the HPLC chromatogram of purified stereoisomer 28(S,R).

[0038]FIG. 16 depicts HPLC traces for various mixtures comprising acompound prepared according to the methods of the present invention.

[0039]FIG. 17 depicts HPLC traces for various mixtures comprising acompound prepared according to the methods of the present invention.

[0040]FIG. 18 depicts HPLC traces for various mixtures comprising acompound prepared according to the methods of the present invention.

[0041]FIG. 19 depicts HPLC traces for various mixtures comprising acompound prepared according to the methods of the present invention.

[0042]FIG. 20 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0043]FIG. 21 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0044]FIG. 22 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0045]FIG. 23 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0046]FIG. 24 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0047]FIG. 25 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0048]FIG. 26 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0049]FIG. 27 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0050]FIG. 28 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0051]FIG. 29 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0052]FIG. 30 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0053]FIG. 31 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0054]FIG. 32 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0055]FIG. 33 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0056]FIG. 34 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0057]FIG. 35 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0058]FIG. 36 depicts various asymmetric ligands that may be comprisedby the asymmetric catalysts utilized in the asymmetric synthetic methodsof the present invention.

[0059]FIG. 37 depicts various sources of nucleophilic carbon that may beutilized in the asymmetric synthetic methods of the present invention.

[0060]FIG. 38 depicts various sources of nucleophilic carbon that may beutilized in the asymmetric synthetic methods of the present invention.

[0061]FIG. 39 depicts an ORTEP drawing of the X-ray crystal structure ofcompound 2.

[0062]FIG. 40 depicts an HPLC chromatogram of a mixture of stereoisomers1, 2, 3, and 4.

[0063]FIG. 41 depicts the HPLC chromatogram of purified stereoisomer 2(R,S).

DETAILED DESCRIPTION OF THE INVENTION

[0064] Pain is an unpleasant sensation varying in severity in a localpart of the body or several parts of the body resulting from injury,disease, or emotional disorder. Pain can be classified according to itsduration. Acute pain, which lasts less than one month, usually has areadily identifiable cause (e.g., hip fracture) and signals tissuedamage. The associated effect is often anxiety, and the concomitantphysiologic findings are those of sympathetic stimulation (e.g.,tachycardia, tachypnea, diaphoresis). In addition, acute pain syndromescan be episodic, for example recurrent discomfort from arthritis.

[0065] Chronic pain can be defined as pain that persists more than onemonth beyond the usual course of an acute illness or injury, or painthat recurs at intervals over months or years, or pain that isassociated with a chronic pathologic process. In contrast to acute pain,chronic pain loses its adaptive biologic function. Depression is common,and abnormal illness behavior often compounds the patient's impairment.Chronic pain can be divided broadly into that which is inferred to bepredominantly somatogenic and that which is inferred to be predominantlypsychogenic. A similar classification based on inferred pathophysiologydesignates chronic pain as nociceptive (commensurate with ongoingactivation of pain-sensitive nerve fibers), neuropathic (due to aberrantsomatosensory processing in afferent neural pathways), or psychogenic.

[0066] Nociceptive pain can be somatic or visceral. Most chronic pain inthe elderly is nociceptive and somatic; arthritis, cancer pain, andmyofascial pain are most common. Relief is likely with removal of theperipheral cause (e.g., reducing periarticular inflammation), andanalgesic drugs are often effective.

[0067] A common subtype of neuropathic pain, known collectively asperipheral neuropathic pain, is presumably sustained by mechanisms thatinvolve disturbances in the peripheral nerve or nerve root; neuromaformation after axonal injury and nerve compression are the two majorprocesses. Another subtype of neuropathic pain is related to thereorganization of nociceptive information processing by the CNS; itpersists without ongoing activation of pain-sensitive fibers. This typeof pain, known collectively as the deafferentation syndromes, includespostherpetic neuralgia, central pain (which can result from a lesion atany level of the CNS), phantom limb pain, and others. A third subtype ofneuropathic pain, often called sympathetically maintained pain, can beameliorated by interruption of sympathetic nerves to the painful area;the prototypic disorder is reflex sympathetic dystrophy. The precisemechanisms involved in these disorders are conjectural, but all canproduce an unfamiliar pain, often described as burning and stabbing.Currently, this type of pain responds poorly to analgesics.

[0068] Some patients have persistent pain without either nociceptivefoci or evidence of a neuropathic mechanism for the pain. Many othershave nociceptive lesions that do not sufficiently explain the degree ofpain and disability. Psychopathologic processes account for thesecomplaints in some patients. If no evidence for a psychological cause isfound, the pain is referred to as idiopathic. Many patients have anidiopathic pain syndrome that is best described by the generic diagnosischronic nonmalignant pain syndrome, a term denoting pain and disabiltdisproportionate to an identifiable somatic cause and usua relted to amore pervasive set of abnormal illness behaviors. Some of these patientsmay be labeled by the more formal psychiatric diagnosis of somatoformpain disorder. Others have complaints that constitute a specific paindiagnosis, most commonly the failed low back syndrome or atypical facialpain. Still others have significant organic lesions (e.g., lumbararachnoiditis) but also have a clear psychological contributionassociated with excessive disability. Diagnosis may be difficult, butthe relative contributions of both organic and psychological componentsof the pain can be defined.

[0069] Another clinically useful classification of chronic pain isbroadly syndromic. For example, chronic pain may be part of a medicalillness (e.g., cancer or arthritis). A mixture of pathophysiologicmechanisms may be involved; e.g., tumor invasion of nerve and bone maycause neuropathic and somatic nociceptive pains, respectively, andpsychological factors may be prominent.

[0070] Three general classes of drugs are currently available for painmanagement, nonsteriodal anti-inflammatories, opioids, and adjuvantanalgesics. The nonsteriodal anti-inflammatories class includes drugssuch as aspirin, ibuprofen, diclofenac, acetaminophen, and rofecoxib.The opioid class includes morphine, oxycodone, fentanyl, andpentazocine. Adjuvant analgesics include various antidepressants,anticonvulsants, neuroleptics, and corticosteroids.

[0071] Of the three classes of pharmaceutical agents used for painmanagement, opioid are usually most efficacious for treating moderate tosevere pain. Although opioids can be very effective in pain management,they do cause several side effects, such as respiratory depression,constipation, physical dependence, tolerance, withdraw. These unwantedeffects can severely limit their use. Therefore, there is a current needfor pharmaceutical agents that retain the analgesic properties of theknown opioid, but have reduced side effect profiles for the treatment ofpain.

[0072] Opioids, specifically ligands for the μ-opioid receptor, are themajor class of analgesics used in the management of moderate to severepain because of their effectiveness, ease of titration, and favorablerisk-to-benefit ratio. Unfortunately, the opioids currently availablehave several unwanted side-effects, such as respiratory depression andconstipation. In addition, these agents may-lead to tolerance anddependence. Research into the development of new, selective ligands foropioid receptors holds the promise of yielding potent analgesics thatlack the side effects of morphine and its congeners. Applicants hereindisclose novel analgesics, including selective ligands for opioidreceptors. Individual compounds described herein promise to haveagonistic, antagonistic, and hybrid effects on opioid and other cellularreceptors. Additionally, new compounds reported herein may possessanalgesic properties free from respiratory depression and the potentialfor physical dependence associated with μ-opioid receptor ligands, suchas morphine and fentanyl. Moreover, new compounds reported herein maypossess properties for the treatment of physical or psychologicaladditions, psychiatric disorders, and neurological pathologies, such astinnitus.

[0073] The μ-opioid receptor is a member of a family of cell surfaceproteins that permit intracellular transduction of extracellularsignals. Cell surface proteins provide eukaryotic and prokaryotic cellsa means to detect extracellular signals and transduce such signalsintracellularly in a manner that ultimately results in a cellularresponse or a concerted tissue or organ response. Cell surface proteins,by intracellularly transmitting information regarding the extracellularenvironment via specific intracellular pathways induce an appropriateresponse to a particular stimulus. The response may be immediate andtransient, slow and sustained, or some mixture thereof. By virtue of anarray of varied membrane surface proteins, eukaryotic cells areexquisitely sensitive to their environment.

[0074] Definitions

[0075] For convenience, certain ten-ns employed in the specification,examples, and appended claims are collected here.

[0076] The term “heteroatom” as used herein means an atom of any elementother than carbon or hydrogen. Preferred heteroatoms are boron,nitrogen, oxygen, phosphorus, sulfur and selenium.

[0077] The term “electron-withdrawing group” is recognized in the art,and denotes the tendency of a substituent to attract valence electronsfrom neighboring atoms, i.e., the substituent is electronegative withrespect to neighboring atoms. A quantification of the level ofelectron-withdrawing capability is given by the Hammett sigma (σ)constant. This well known constant is described in many references, forinstance, J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1977 edition) pp. 251-259. The Hammett constantvalues are generally negative for electron donating groups (σ[P]=−0.66for NH2) and positive for electron withdrawing groups (σ[P]=0.78 for anitro group), σ[P] indicating para substitution. Exemplaryelectron-withdrawing groups include nitro, acyl, formyl, sulfonyl,trifluoromethyl, cyano, chloride, and the like. Exemplaryelectron-donating groups include amino, methoxy, and the like.

[0078] The term “alkyl” refers to the radical of saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In preferredembodiments, a straight chain or branched chain alkyl has 30 or fewercarbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀for branched chain), and more preferably 20 or fewer. Likewise,preferred cycloalkyls have from 3-10 carbon atoms in their ringstructure, and more preferably have 5, 6 or 7 carbons in the ringstructure.

[0079] Unless the number of carbons is otherwise specified, “loweralkyl” as used herein means an alkyl group, as defined above, but havingfrom one to ten carbons, more preferably from one to six carbon atoms inits backbone structure. Likewise, “lower alkenyl” and “lower alkynyl”have similar chain lengths. Preferred alkyl groups are lower alkyls. Inpreferred embodiments, a substituent designated herein as alkyl is alower alkyl.

[0080] The term “aralkyl”, as used herein, refers to an alkyl groupsubstituted with an aryl group (e.g., an aromatic or heteroaromaticgroup).

[0081] The terms “alkenyl” and “alkynyl” refer to unsaturated aliphaticgroups analogous in length and possible substitution to the alkylsdescribed above, but that contain at least one double or triple bondrespectively.

[0082] The term “aryl” as used herein includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. Those aryl groups having heteroatoms inthe ring structure may also referred to as “aryl heterocycles” or“heteroaromatics.” The aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,alkoxyl, amino, nitro, sulffiydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN, or the like. The terrn “aryl” alsoincludes polycyclic ring systems having two or more cyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein at least one of the rings is aromatic, e.g.,the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls.

[0083] The terms ortho, meta and para apply to 1,2-, 1,3- and1,4-disubstituted benzenes, respectively. For example, the names1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

[0084] The terms “heterocyclyl” or “heterocyclic group” refer to 3- to10-membered ring structures, more preferably 3- to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocycles canalso be polycycles. Heterocyclyl groups include, for example, thiophene,thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

[0085] The terms “polycyclyl” or “polycyclic group” refer to two or morerings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused-rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryr, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF₃, —CN, or the like.

[0086] The term “(R)-2-Methyl-CBS-oxazaborolidine” and its systematicname“(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole”refer to the following reagent:

[0087] The term “(S)-2-Methyl-CBS-oxazaborolidine” and its systematicname“(S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole”refer to the following reagent:

[0088] As used herein, the term “nitro” means —NO₂; the term “halogen”designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂—.

[0089] The terms “amine” and “amino” are art-recognized and refer toboth unsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

[0090] wherein R₉, R₁₀ and R′ 10 each independently represent a grouppermitted by the rules of valence.

[0091] The term “acylamino” is art-recognized and refers to a moietythat can be represented by the general formula:

[0092] wherein R₉ represents a group permitted by the rules of valence,and R′₁₁ represents hydrogen, alkyl, cycloalkyl, alkenyl, aryl,heteroaryl, aralkyl, or heteroaralkyl.

[0093] The term “amido” is art recognized as an amino-substitutedcarbonyl and includes a moiety that can be represented by the generalformula:

[0094] wherein R₉, R₁₀ are as defined above. Preferred embodiments ofthe amide will not include imides which may be unstable.

[0095] The term “alkylthio” refers to an alkyl group, as defined above,having a sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, and—S-alkynyl. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0096] The term “carbonyl” is art recognized and includes such moietiesas can be represented by the general formula:

[0097] wherein X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₈ or apharmaceutically acceptable salt, R₁₁ represents a hydrogen, an alkyl,an alkeri-y or —(CH₂)_(m)—R₈, where m and R₈ are as defined above. WhereX is an oxygen and R₁₁ or R₁₁ is not hydrogen, the formula represents an“ester”. Where X is an oxygen, and R₁₁ is as defined above, the moietyis referred to herein as a carboxyl group, and particularly when R₁₁ isa hydrogen, the formula represents a “carboxylic acid”. Where X is anoxygen, and R₁₁ is hydrogen, the formula represents a “formate”. Ingeneral, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiolcarbonyl” group. Where X is asulfur and R₁₁ or R₁₁ is not hydrogen, the formula represents a“thiolester.” Where X is a sulfur and R₁₁ is hydrogen, the formularepresents a “thiolcarboxylic acid.” Where X is a sulfur and R₁₁ ishydrogen, the formula represents a “thiolformate.” On the other hand,where X is a bond, and R₁₁ is not hydrogen, the above formula representsa “ketone” group. Where X is a bond, and R₁₁ is hydrogen, the aboveformula represents an “aldehyde” group.

[0098] The terms “alkoxyl” or “alkoxy” as used herein refers to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,-0-(CH₂)_(m)—R₈,where m and R₈ are described above.

[0099] The term “sulfonate” is art recognized and includes a moiety thatcan be represented by the general formula:

[0100] in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, oraryl.

[0101] The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognizedand refer to trifluoromethanesulfonyl, p-toluenesulfonyl,methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. Theterms triflate, tosylate, mesylate, and nonaflate are art-recognized andrefer to trifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

[0102] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms, Cbz, and Bocrepresent methyl, ethyl, phenyl, trifluoromethanesulfonyl,nonafluorobutanesulfonyl, p-toluenesulfonyl, methanesulfonyl,benzyloxycarbonyl, and t-butyloxycarbonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

[0103] The term “sulfate” is art recognized and includes a moiety thatcan be represented by the general formula:

[0104] in which R₄₁ is as defined above.

[0105] The term “sulfonylamino” is art recognized and includes a moietythat can be represented by the general formula:

[0106] The term “sulfamoyl” is art-recognized and includes a moiety thatcan be represented by the general formula:

[0107] The term “sulfonyl”, as used herein, refers to a moiety that canbe represented by the general formula:

[0108] in which R₄₄ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0109] The term “sulfoxido” as used herein, refers to a moiety that canbe represented by the general formula:

[0110] in which R₄₄ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

[0111] A “selenoalkyl” refers to an alkyl group having a substitutedseleno group attached thereto. Exemplary “selenoethers” which may besubstituted on the alkyl are selected from one of -Se-alkyl,-Se-alkenyl, and -Se-alkynyl.

[0112] Analogous substitutions can be made to alkenyl and alkynyl groupsto produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

[0113] As used herein, the definition of each expression, e.g. alkyl, m,n, etc., when it occurs more than once in any structure, is intended tobe independent of its definition elsewhere in the same structure.

[0114] It will be understood that “substitution” or “substituted with”includes the implicit proviso that such substitution is in accordancewith permitted valence of the substituted atom and the substituent, andthat the substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

[0115] As used herein, the term “substituted” is contemplated to includeall permissible substituents of organic compounds. In a broad aspect,the permissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described herein above. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalences of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

[0116] Thephrase “protecting-group” as seLhereimeans tempora sustituentswhich protect a potentially reactive functional group from undesiredchemical transformations. Examples of such protecting groups includeesters of carboxylic acids, silyl ethers of alcohols, carbamates ofamines, ureas of amines, and acetals and ketals of aldehydes andketones, respectively. The field of protecting group chemistry has beenreviewed (Greene, T. W. Wuts, P.G.M. Protective Groups in OrganicSynthesis, 2^(nd) ed.; Wiley: New York, 1991).

[0117] Certain compounds of the present invention may exist inparticular geometric or stereoisomeric forms. The present inventioncontemplates all such compounds, including cis- and trans-isomers, R-and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

[0118] If, for instance, a particular enantiomer of a compound of thepresent invention is desired, it may be prepared by asymmetricsynthesis, or by derivation with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovide the pure desired enantiomers. Alternatively, where the moleculecontains a basic functional group, such as amino, or an acidicfunctional group, such as carboxyl, diastereomeric salts are formed withan appropriate optically-active acid or base, followed by resolution ofthe diastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

[0119] Contemplated equivalents of the compounds described above includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof (e.g., functioning as analgesics), whereinone or more simple variations of substituents are made which do notadversely affect the efficacy of the compound in binding to opioidreceptors. In general, the compounds of the present invention may beprepared by the methods illustrated in the general reaction schemes as,for example, described below, or by modifications thereof, using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants which are in themselves known, but are not mentioned here.

[0120] For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87, insidecover.

[0121] Compounds of the Invention

[0122] The compounds of the present invention areenantiomerically-enriched substituted pyrrolidines, piperidines, andazepines useful for treatment of numerous ailments, conditions anddiseases that afflict mammals, including but not limited to addictionand pain (see FIG. 1).

[0123] In certain embodiments, a compound of the present invention isrepresented by formula I:

[0124] wherein

[0125] n is 0, 1, or 2;

[0126] R is H, aralkyl, or —CO₂R′;

[0127] R′ is alkyl, aryl, or aralkyl;

[0128] Z is NHR″ or OH; and

[0129] R″ is H, alkyl, aryl, or aralkyl.

[0130] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1.

[0131] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein R isCbz.

[0132] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein R is—CH₂CH₂Ph.

[0133] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein R isH.

[0134] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein R′is methyl.

[0135] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein Z isOH.

[0136] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein Z isNHR″; and R″ is phenyl.

[0137] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; and R is Cbz.

[0138] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; and R′ is Me.

[0139] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R′ is Me; and Z is OH.

[0140] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R′ is Me; Z is OH; and R is Cbz.

[0141] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R′ is Me; Z is NHR″; and R″ is phenyl.

[0142] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R′ is Me; Z is NHR″; R″ is phenyl; and R is Cbz.

[0143] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R is Cbz; and R′ is methyl.

[0144] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; and R is —CH₂CH₂Ph.

[0145] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R is —CH₂CH₂Ph; and R′ is methyl.

[0146] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R is —CH₂CH₂Ph; R′ is methyl; and Z is OH.

[0147] In certain embodiments, the compounds of the present inventionare represented by formula I and the attendant definitions, wherein n is1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ is phenyl.

[0148] In certain embodiments, a compound of the present invention isrepresented by formula II:

[0149] wherein n is 0, 1, or 2;

[0150] R is H, aralkyl, or —CO₂R′;

[0151] R′ is alkyl, aryl, or aralkyl;

[0152] Z is NHR″ or OH; and

[0153] R″ is H, alkyl, aryl, or aralkyl.

[0154] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1.

[0155] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein Ris Cbz.

[0156] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein Ris —CH₂CH₂Ph.

[0157] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein Ris H.

[0158] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein R′is methyl.

[0159] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein Zis OH.

[0160] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein Zis NHR″; and R″ is phenyl.

[0161] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; and R is Cbz.

[0162] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; and R′ is Me.

[0163] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R′ is Me; and Z is OH.

[0164] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R′ is Me; Z is OH; and R is Cbz.

[0165] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R′ is Me; Z is NHR″; and R″ is phenyl.

[0166] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R′ is Me; Z is NHR″; R″ is phenyl; and R is Cbz.

[0167] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R is Cbz; and R′ is methyl.

[0168] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; and R is —CH₂CH₂Ph.

[0169] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; and R′ is methyl.

[0170] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; R′ is methyl; and Z is OH.

[0171] In certain embodiments, the compounds of the present inventionare represented by formula II and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ is phenyl.

[0172] In certain embodiments, a compound of the present invention isrepresented by formula III:

[0173] wherein

[0174] n is 0, 1, or 2;

[0175] R is H, aralkyl, or —CO₂R′;

[0176] R′ is alkyl, aryl, or aralkyl;

[0177] Z is NHR″ or OH; and

[0178] R″ is H, alkyl, aryl, or aralkyl.

[0179] R″ is H, alkyl, aryl, or aralkyl.

[0180] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1.

[0181] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein Ris Cbz.

[0182] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein Ris —CH₂CH₂Ph.

[0183] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein Ris H.

[0184] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein R′is methyl.

[0185] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein Zis OH.

[0186] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein Zis NHR″; and R″ is phenyl.

[0187] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; and R is Cbz.

[0188] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; and R′ is Me.

[0189] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R′ is Me; and Z is OH.

[0190] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R′ is Me; Z is OH; and R is Cbz.

[0191] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R′ is Me; Z is NHR″; and R″ is phenyl.

[0192] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R′ is Me; Z is NHR″; R″ is phenyl; and

[0193] R is Cbz.

[0194] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R is Cbz; and R′ is methyl.

[0195] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; and R is —CH₂CH₂Ph.

[0196] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; and R′ is methyl.

[0197] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; R′ is methyl; and Z is OH.

[0198] In certain embodiments, the compounds of the present inventionare represented by formula III and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ is phenyl.

[0199] In certain embodiments, a compound of the present invention isrepresented by formula IV:

[0200] wherein

[0201] n is 0, 1, or 2;

[0202] R is H, aralkyl, or —CO₂R′;

[0203] R′ is alkyl, aryl, or aralkyl;

[0204] Z is NHR″ or OH; and

[0205] R″ is H, alkyl, aryl, or aralkyl.

[0206] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1.

[0207] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein Ris Cbz.

[0208] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein Ris —CH₂CH₂Ph.

[0209] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein Ris H.

[0210] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein R′is methyl.

[0211] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein Zis OH.

[0212] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein Zis NHR″; and R″ is phenyl.

[0213] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; and R is Cbz.

[0214] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; and R′ is Me.

[0215] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R′ is Me; and Z is OH.

[0216] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R′ is Me; Z is OH; and R is Cbz.

[0217] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R′ is Me; Z is NHR″; and R″ is phenyl.

[0218] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R′ is Me; Z is NHR″; R″ is phenyl; and R is Cbz.

[0219] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R is Cbz; and R′ is methyl.

[0220] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; and R is —CH₂CH₂Ph.

[0221] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; and R′ is methyl.

[0222] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; R′ is methyl; and Z is OH.

[0223] In certain embodiments, the compounds of the present inventionare represented by formula IV and the attendant definitions, wherein nis 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ is phenyl.

[0224] Methods of the Invention

[0225] One aspect of the present invention relates to syntheticprocedures for the enantio- and diastereo-selective syntheses of each ofthe four stereoisomeric compounds 1, 2, 3 and 4, which procedures aredescribed herein.

[0226] Several synthetic routes have been envisioned by the inventors,including several that start from 3-acylpyridine and include astereoselective reduction of the acyl carbonyl to substantially oneenantiomer of an alcohol (see FIGS. 2-4). One synthetic route inparticular is described in greater detail below and starts fromsubstantially one enantiomer of a 3-ester substituted cyclic amine. Thesynthetic route converts the ester to an aldehyde followed by astereoselective nucleophilic addition to the aldehyde to producesubstantially one enantiomer of an alcohol (see FIGS. 5 and 6).

[0227] In general, the first stereocenter (“A”) may be obtainedenantiopure in the form of a commercially available tartrate salt ofethyl nipecotate. For example, commercially available (R)-ethylnipecotate is typically an (1)-tartaric acid (5); whereas, commerciallyavailable (S)-ethyl nipecotate is typically a (d)-tartaric acid salt(6).

[0228] Enantiopure esters 5 and 6 were taken forward to aldehydes 9 and12 following the reaction scheme outlined below. Amines 5 and 6 wereprotected as carbamates 7 and 10, respectively. Other protecting groupsthat render the amine non-basic are anticipated to be acceptable.

[0229] Reduction of the ester by either a one-step or two-step protocolprovided alcohols 8 and 11. For the one step procedure, treatment ofesters 7 and 10 with lithium aluminum hydride provided the desiredalcohols 8 and 11, respectively.

[0230] For the two-step procedure, ester hydrolysis to the acid followedby borane-dimethyl sulfide reduction provided alcohols 8 and 11. Othercommonly employed reagents for the conversion of these intermediates tothe alcohol are anticipated to be acceptable.

[0231] aldehydes 9 and 12 can be obtained using a variety of reactionconditions commonly used for such transformations. For example, it isanticipated that the esters (7 and 10), acids (25 and 26) orcorresponding acid halides could be converted directly to aldehydes 9and 12.

[0232] Aldehydes 9 and 12 were synthesized from alcohols 8 and 11 bySwem oxidation. Aldehyde 9 was also obtained by Dess-Martin oxidation.It is anticipated that Dess-Martin oxidation could be used to convertalcohol 11 to aldehyde 12 equally well. Other commonly used oxidantssuch as such as pyridinium chlorochromate are also anticipated to workfor this transformation.

[0233] The second stereocenter of the piperidines (“B”) was selectivelyinstalled utilizing a diastereoselective addition of dimethylzinccatalyzed by the TADDOL catalyst, developed by D. Seebach (J. L. von demBussche-Hunnefeld and D. Seebach, Tetrahedron, 1992, 48(27), 5719), toaldehydes 9 and 12. Among other catalysts, the TADDOL catalyst withAr=Phenyl and 1-naphthyl was effective; however, even better resultswere achieved with the TADDOL catalyst wherein Ar=2-naphthyl. Bychoosing the correct TADDOL catalyst enantiomer (13 or 14), product witheither the (S)-(15) or (R)-(16) configuration for stereocenter “B” wasachieved. Assignment of stereochemistry was made based on literatureprecedents. Catalyst 13 promotes addition to the si face to form 15 (RS)and 27 (SS) from aldehydes 9 and 12, respectively; whereas, catalyst 14promotes addition to the re face to form alcohol 16 (RR) and 28 (SR)from aldehydes 9 and 12, respectively.

[0234] In certain embodiments, the use of about 5 mol % to about 20 mol% TADDOL is preferred. In certain embodiments, the use of about 15 mol %TADDOL is preferred. In certain embodiments, the use of about 10 mol %TADDOL is preferred. In certain embodiments, the use of freshlydistilled titanium tetraisopropoxide and dimethyl zinc is preferred.Furthermore, catalyst derived from recovered TADDOL ligand may be usedwith no loss in yields and selectivities.

[0235] It is anticipated that other chiral catalysts and reagentsdesigned to stereoselectively add alkyl groups, such as methyl, toaldehydes will work in the methods of the present invention. For arecent review, which is hereby expressly incorporated by reference, see:Pu, L, Yu, H.-B. “Catalytic Asymmetric Organozinc Additions to CarbonylCompounds” Chem. Rev. 2001, 101, 757-824. In other words, many differentchiral ligands may be used in conjunction with a transition metal tocatalyze this transformation. Examples of such catalysts and/or ligandsinclude chiral amino alcohols, chiral iminyl alcohols, chiral aminothiols, chiral disulfides, chiral diselenides, chiral amines, chiraldiols, chiral sulfonamides, chiral phosphoramides, chiral ligandsattached to solid supports, chiral dendrites, and chiral polymers.Various examples of each type of ligand are depicted in FIGS. 20-36. Thecatalysts for this transformation may be isolated or generated in situby a complex of any of the above ligands with titanium, zinc, iron,ruthenium, chromium, zirconium, nobium, manganese, lead, calcium, boron,lithium, cadmium, aluminum, tin, or copper. There are many sources ofnucleophilic carbon for this transformation, e.g., dimethyl zinc;various examples of nucleophilic carbon sources are depicted in FIGS. 37and 38.

[0236] Once both stereocenters are established, completion of thesynthesis to selectively form 1, 2, 3 and 4 is straightforward (seeFIGS. 7-10). Alcohols 15, 16, 27 and 28 were converted to thecorresponding mesylates with mesyl chloride. SN2 displacement withaniline provided amines 17, 19, 33 and 34, respectively. No loss ofenantiopurity was observed for the aniline displacement reaction.

[0237] The conversion of the alcohols to the corresponding amines canalso be accomplished by conversion of the alcohol to a triflate, withsubsequent SN2 displacement by aniline. This alternative protocol wasdemonstrated by the conversion of alcohol 15 to amine 17. Thistransformation has been run in one pot without isolation or purificationof the triflate intermediate. Furthermore, the amine product was easilyobtained with high levels of purity, allowing for higher yields in thesubsequent acylation step described below.

[0238] Acylation of amines 17, 19, 33, and 34 with propionyl chlorideprovided amides 18, 20, 35 and 36. Acylation with other reagents such aspropionic anhydride or propionic acids activated with a reagent such asPyBOP are also anticipated to work for this transformation.

[0239] Cbz deprotection was straightforward, as was represented by theconversions of 18 and 20 to secondary amines 37 and 38.

[0240] These secondary amines may be converted to a variety of products,such as amides, sulfonamides, ureas, and carbamates. In certainpreferred embodiments, the secondary amines are converted to tertiaryamine products, such as compounds 1, 2, 3 and 4. In the case of 1-4,treatment with a phenethylhalide and a base such as K₂CO₃ may be used.This was demonstrated by the chemistry described below for the synthesisof a mixture of 1-4. Of course, one of ordinary skill in the art oforganic chemistry will recognize that other methods, e.g., reductiveamination, may be used to achieve these alkylations.

[0241] As was noted above, it is anticipated that the chemistriesdescribed above should work well with BOC protected amine compounds.This was demonstrated in the non-selective synthesis of 24, a mixture ofisomers 1-4. 24 was synthesized from alcohol 21, which differs from 15and 16 only in its carbamate protecting group (BOC instead of Cbz), andits lack of enantio- and diastereo-purity. Compound 21 was obtained byGrignard addition to the corresponding aldehyde. For the stereoselectivechemistry described above, N-Cbz protection was chosen over N-BOCprotection based only on the fact that the Cbz-compounds have a betterchromophore (compared to BOC protected compounds) for analytical HPLC eeand de determinations of intermediates on the route to compounds 1 to 4.

[0242] Compound 24 was separated into the four individual isomers, 1-4,by achiral and chiral chromatographic methods. Furthermore, all fourisomers (1-4) were separated by analytical chiral HPLC methods. Theabsolute stereochemistry of all four isomers (obtained by separation of24) was determined using x-ray crystallographic and other analyticalmethods. The absolute stereochemistry of 2 was determined by x-raycrystallography. FIG. 39. This information was then combined with otheranalytical methods to determine the absolute stereochemistry of all fourisomers (1 to 4). Using these authentic samples, the stereochemistryassigned for the products 15, 16, 27 and 28 were confirmed. AnalyticalHPLC comparison of 2, synthesized stereoselectively by the methodsdescribed herein, matched the known sample of 2, synthesized byseparation of 24.

[0243] Combinatorial Libraries

[0244] The subject methods may be practiced in a combinatorial sense toprepare combinatorial libraries of substituted piperidines for thescreening of pharmaceutical, agrochemical or other biological ormedically-related activity or material-related qualities. Acombinatorial library for the purposes of the present invention is amixture of chemically related compounds which may be screened togetherfor a desired property; said libraries may be in solution or covalentlylinked to a solid support. The preparation of many related compounds ina single reaction greatly reduces and simplifies the number of screeningprocesses which need to be carried out. Screening for the appropriatebiological, pharmaceutical, agrochemical or physical property may bedone by conventional methods.

[0245] Diversity in a library can be created at a variety of differentlevels. For instance, the substrate aryl groups used in a combinatorialapproach can be diverse in terms of the core aryl moiety, e.g., avariegation in terms of the ring structure, and/or can be varied withrespect to the other substituents.

[0246] A variety of techniques are available in the art for generatingcombinatorial libraries of small organic molecules. See, for example,Blondelle et al. (1995) Trends Anal. Chem. 14:83; the Affymax U.S. Pat.Nos. 5,359,115 and 5,362,899: the Ellman U.S. Pat. No. 5,288,514: theStill et al. PCT publication WO 94/08051; Chen et al. (1994) JACS116:2661: Kerr et al. (1993) JACS 115:252; PCT publications WO92/10092,WO93/09668 and WO91/07087; and the Lemer et al. PCT publicationWO93/20242). Accordingly, a variety of libraries on the order of about16 to 1,000,000 or more diversomers can be synthesized and screened fora particular activity or property embodiment, a library of substituteddiversomers can be synthesized using the subject reactions adapted tothe techniques described in the Still et al. PCT publication WO94/08051, e.g., being linked to a polymer bead by a hydrolyzable orphotolyzable group, e.g., located at one of the positions of substrate.According to the Still et al. technique, the library is synthesized on aset of beads, each bead including a set of tags identifying theparticular diversomer on that bead. In one embodiment, which isparticularly suitable for discovering enzyme inhibitors, the beads canbe dispersed on the surface of a permeable membrane, and the diversomersreleased from the beads by lysis of the bead linker. The diversomer fromeach bead will diffuse across the membrane to an assay zone, where itwill interact with an enzyme assay. Detailed descriptions of a number ofcombinatorial methodologies are provided below.

[0247] A. Direct Characterization

[0248] A growing trend in the field of combinatorial chemistry is toexploit the sensitivity of techniques such as mass spectrometry (MS),e.g., which can be used to characterize sub-femtomolar amounts of acompound, and to directly determine the chemical constitution of acompound selected from a combinatorial library. For instance, where thelibrary is provided on an insoluble support matrix, discrete populationsof compounds can be first released from the support and characterized byMS. In other embodiments, as part of the MS sample preparationtechnique, such MS techniques as MALDI can be used to release a compoundfrom the matrix, particularly where a labile bond is used originally totether the compound to the matrix. For instance, a bead selected from alibrary can be irradiated in a MALDI step in order to release thediversomer from the matrix, and ionize the diversomer for MS analysis.

[0249] B) Multipin Synthesis

[0250] The libraries of the subject method can take the multipin libraryformat. Briefly, Geysen and co-workers (Geysen et al. (1984) PNAS81:3998-4002) introduced a method for generating compound libraries by aparallel synthesis on polyacrylic acid-grated polyethylene pins arrayedin the microtitre plate format. The Geysen technique can be used tosynthesize and screen thousands of compounds per week using the multipinmethod, and the tethered compounds may be reused in many assays.Appropriate linker moieties can also been appended to the pins so thatthe compound after synthesis for assessment of purity and furtherevaluation (c.f., Bray et al. (1990) Tetrahedron Lett 31:5811-5814;Valerio et al. (1991) Anal Biochem 197:168-177; Bray et al. (1991)Tetrahedron Lett 32:6163-6166).

[0251] C) Divide-Couple-Recombine

[0252] In yet another embodiment, a variegated library of compounds canbe provided on a set of beads utilizing the strategy ofdivide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135;and U.S. Pat. Nos. 4,631,211; 5,440,016; 5,480,971). Briefly, as thename implies, at each synthesis step where degeneracy is introduced intothe library, the beads are divided into separate groups equal to thenumber of different substituents to be added at a particular position inthe library, the different substituents coupled in separate reactions,and the beads recombined into one pool for the next iteration.

[0253] In one embodiment, the divide-couple-recombine strategy can becarried out using an analogous approach to the so-called “tea bag”method first developed by Houghten, where compound synthesis occurs onresin sealed inside porous polypropylene bags (Houghten et al. (1986)PNAS 82:5131-5135). Substituents are coupled to the compound-bearingresins by placing the bags in appropriate reaction solutions, while allcommon steps such as resin washing and deprotection are performedsimultaneously in one reaction vessel. At the end of the synthesis, eachbag contains a single compound.

[0254] D) Combinatorial Libraries by Light-Directed, SpatiallyAddressable Parallel Chemical Synthesis

[0255] A scheme of combinatorial synthesis in which the identity of acompound is given by its locations on a synthesis substrate is termed aspatially-addressable synthesis. In one embodiment, the combinatorialprocess is carried out by controlling the addition of a chemical reagentto specific locations on a solid support (Dower et al. (1991) Annu RepMed Chem 26:271-280; Fodor, S.P.A. (1991) Science 251:767; Pirrung etal. (1992) U.S. Pat. No. 5,143,854; Jacobs et al. (1994) TrendsBiotechnol 12:19-26). The spatial resolution of photolithography affordsminiaturization. This technique can be carried out through the useprotection/deprotection reactions with photolabile protecting groups.

[0256] The key points of this technology are illustrated in Gallop etal. (1994) J Med Chem 37:1233-1251. A synthesis substrate is preparedfor coupling through the covalent attachment of photolabilenitroveratryloxycarbonyl (NVOC) protected amino linkers or otherphotorabile linkers. Light is used to selectively activate a specifiedregion of the synthesis support for coupling. Removal of the photolabileprotecting groups by light (deprotection) results in activation ofselected areas. After activation, the first of a set of amino acidanalogs, each bearing a photolabile protecting group on the aminoterminus, is exposed to the entire surface. Coupling only occurs inregions that were addressed by light in the preceding step. The reactionis stopped, the plates washed, and the substrate is again illuminatedthrough a second mask, activating a different region for reaction with asecond protected building block. The pattern of masks and the sequenceof reactants define the products and their locations. Since this processutilizes photolithography techniques, the number of compounds that canbe synthesized is limited only by the number of synthesis sites that canbe addressed with appropriate resolution. The position of each compoundis precisely known; hence, its interactions with other molecules can bedirectly assessed.

[0257] In a light-directed chemical synthesis, the products depend onthe pattern of illumination and on the order of addition of reactants.By varying the lithographic patterns, many different sets of testcompounds can be synthesized simultaneously; this characteristic leadsto the generation of many different masking strategies.

[0258] E) Encoded Combinatorial Libraries

[0259] In yet another embodiment, the subject method utilizes a compoundlibrary provided with an encoded tagging system. A recent improvement inthe identification of active compounds from combinatorial librariesemploys chemical indexing systems using tags that uniquely encode thereaction steps a given bead has undergone and, by inference, thestructure it carries. Conceptually, this approach mimics phage displaylibraries, where activity derives from expressed peptides, but thestructures of the active peptides are deduced from the correspondinggenomic DNA sequence. The first encoding of synthetic combinatoriallibraries employed DNA as the code. A variety of other forms of encodinghave been reported, including encoding with sequenceable bio-oligomers(e.g., oligonucleotides and peptides), and binary encoding withadditional non-sequenceable tags.

[0260] 1) Tagging with Sequenceable Bio-Oligomers

[0261] The principle of using oligonucleotides to encode combinatorialsynthetic libraries was described in 1992 (Brenher et al; (1992) PNAS89:5381-5383), and an example of such a library appeared the followingyear (Needles et al. (1993) PNAS 90:10700-10704). A combinatoriallibrary of nominally 77 (=823,543) peptides composed of all combinationsof Arg, Gln, Phe, Lys, Val, D-Val and Thr (three-letter amino acidcode), each of which was encoded by a specific dinucleotide (TA, TC, CT,AT, TT, CA and AC, respectively), was prepared by a series ofalternating rounds of peptide and oligonucleotide synthesis on solidsupport. In this work, the amine linking functionality on the bead wasspecifically differentiated toward peptide or oligonucleotide synthesisby simultaneously preincubating the beads with reagents that generateprotected OH groups for oligonucleotide synthesis and protected NH2groups for peptide synthesis (here, in a ratio of 1:20). When complete,the tags each consisted of 69-mers, 14 units of which carried the code.The bead-bound library was incubated with a fluorescently labeledantibody, and beads containing bound antibody that fluoresced stronglywere harvested by fluorescence-activated cell sorting (FACS). The DNAtags were amplified by PCR and sequenced, and the predicted peptideswere synthesized. Following such techniques, compound libraries can bederived for use in the subject method, where the oligonucleotidesequence of the tag identifies the sequential combinatorial reactionsthat a particular bead underwent, and therefore provides the identity ofthe compound on the bead.

[0262] The use of oligonucleotide tags permits exquisitely sensitive taganalysis. Even so, the method requires careful choice of orthogonal setsof protecting groups required for alternating co-synthesis of the tagand the library member. Furthermore, the chemical lability of the tag,particularly the phosphate and sugar anomeric linkages, may limit thechoice of reagents and conditions that can be employed for the synthesisof non-oligomeric libraries. In preferred embodiments, the librariesemploy linkers permitting selective detachment of the test compoundlibrary member for assay.

[0263] Peptides have also been employed as tagging molecules forcombinatorial libraries. Two exemplary approaches are described in theart, both of which employ branched linkers to solid phase upon whichcoding and ligand strands are alternately elaborated. In the firstapproach (Kerr J M et al. (1993) J Am Chem Soc 115:2529-2531),orthogonality in synthesis is achieved by employing acid-labileprotection for the coding strand and base-labile protection for thecompound strand.

[0264] In an alternative approach (Nikolaiev et al. (1993) Pept Res6:161-170), branched linkers are employed so that the coding unit andthe test compound can both be attached to the same functional group onthe resin. In one embodiment, a cleavable linker can be placed betweenthe branch point and the bead so that cleavage releases a moleculecontaining both code and the compound (Ptek et al. (1991) TetrahedronLett 32:3891-3894). In another embodiment, the cleavable linker can beplaced so that the test compound can be selectively separated from thebead, leaving the code behind. This last construct is particularlyvaluable because it permits screening of the test compound withoutpotential interference of the coding groups. Examples in the art ofindependent cleavage and sequencing of peptide library members and theircorresponding tags has confirmed that the tags can accurately predictthe peptide structure.

[0265] 2) Non-sequenceable Tagging: Binary Encoding

[0266] An alternative form of encoding the test compound library employsa set of non-sequencable electrophoric tagging molecules that are usedas a binary code (Ohlmeyer et al. (1993) PNAS 90:10922-10926). Exemplarytags are haloaromatic alkyl ethers that are detectable as theirtrimethylsilyl ethers at less than femtomolar levels by electron capturegas chromatography (ECGC). Variations in the length of the alkyl chain,as well as the nature and position of the aromatic halide substituents,permit the synthesis of at least 40 such tags, which in principle canencode 240 (e.g., upwards of 10¹²) different molecules. In the originalreport (Ohlmeyer et al., supra) the tags were bound to about 1% of theavailable amine groups of a peptide library via a photocleavableo-nitrobenzyl linker. This approach is convenient when preparingcombinatorial libraries of peptide-like or other amine-containingmolecules. A more versatile system has, however, been developed thatpermits encoding of essentially any combinatorial library. Here, thecompound would be attached to the solid support via the photocleavablelinker and the tag is attached through a catechol ether linker viacarbene insertion into the bead matrix (Nestler et al. (1994) J Org Chem59:4723-4724). This orthogonal attachment strategy permits the selectivedetachment of library members for assay in solution and subsequentdecoding by ECGC after oxidative detachment of the tag sets.

[0267] Although several amide-linked libraries in the art employ binaryencoding with the electrophoric tags attached to amine groups, attachingthese tags directly to the bead matrix provides far greater versatilityin the structures that can be prepared in encoded combinatoriallibraries. Attached, linker are nearhly as unreactive as the bead matrixitself. Two binary-encoded combinatorial libraries have been reportedwhere the electrophoric tags are attached directly to the solid phase(Ohlmeyer et al. (1995) PNAS 92:6027-6031) and provide guidance forgenerating the subject compound library. Both libraries were constructedusing an orthogonal attachment strategy in which the library member waslinked to the solid support by a photolabile linker and the tags wereattached through a linker cleavable only by vigorous oxidation. Becausethe library members can be repetitively partially photoeluted from thesolid support, library members can be utilized in multiple assays.Successive photoelution also permits a very high throughput iterativescreening strategy: first, multiple beads are placed in 96-wellmicrotiter plates; second, compounds are partially detached andtransferred to assay plates; third, a metal binding assay identifies theactive wells; fourth, the corresponding beads are rearrayed singly intonew microtiter plates; fifth, single active compounds are identified;and sixth, the structures are decoded.

Exemplification

[0268] The invention now being generally described, it will be morereadily understood by reference to the following examples, which areincluded merely for purposes of illustration of certain aspects andembodiments of the present invention, and are not intended to limit theinvention.

Example 1

[0269] Synthesis of (3R)-Piperidine-113-dicarboxylic acid 1-benzyl ester3-ethyl ester (7)

[0270] Protocol 1

[0271] (R)-Ethyl nipecotate-(O)-tartrate salt (15.0 g, 48.81 mmol) wasdissolved in 61 mL of 3:1 THF: H₂O, and the solution was stirred underN₂ at 0° C. 20.24 g (146.4 mmol) of K₂CO₃ was added in one portion, then8.33 mL (51.25 mmol) of (benzyoxy)carbonyl chloride was added dropwise.The reaction was allowed to warm to room temperature with stirringovernight. The solvent was then removed, and EtOAc and H₂O were added.The organic layer was separated, washed with brine, dried with sodiumsulfate, filtered, and concentrated. The crude material was used withoutfurther purification.

[0272] Protocol 2

[0273] A 1.0 L round-bottom flask was charged with K₂CO₃ (29.2 g; 171mmol), piperidine (50 g; 163 mmol), and a 1:1 mixture of THF/H₂O (800mL). A 150 mL addition funnel was placed on the flask and charged withCbzCl (29.2 g, 171 mmol). The flask was cooled to 0° C. and then CbzClwas added dropwise over 5 minutes. The reaction mixture was warmed to20° C. and stirred for 1 h. The reaction mixture was extracted withEtOAc (500 mL) and the organic layer was washed with water (500 mL),saturated NaCl (500 mL), dried (MgSO₄), filtered and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, hexanes/EtOAc 9:1 to 4:1) to give pure product (49.3 g, 100%yield). ¹H-NMR (300 MHz)δ(ppm) 7.40 (m; 5H); 5.17 (s; 2H); 4.19 (q; 2H);4.04 (m; 1H); 3.12 (m; 1H); 2.95 (m; 1H); 2.48 (m; 1H); 2.08 (m; 1H);1.75 (m; 3H); 1.53 (m; 1H); 1.28 (t; 3H).

Example 2

[0274] Synthesis of (3S)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester3-ethyl ester (10)

[0275] A 1.0 L round-bottom flask was charged with K₂CO₃ (29.2 g; 171mmol), piperidine (50 g; 163 mmol), and a 1:1 mixture of THF/H₂O (800mL). A 150 mL addition funnel was placed on the flask and charged withCbzCl (29.2 g, 171 mmol). The flask was cooled to 0° C. and then CbzClwas added dropwise over 5 minutes. The reaction mixture was warmed to20° C. and stirred for 1 h. The reaction mixture was extracted withEtOAc (500 mL) and the organic layer was washed with water (500 mL),saturated NaCl (500 mL), dried (MgSO₄), filtered and concentrated invacuo. The crude material (49.3 g, 100% yield) was carried on withoutfurther purification.

Example 3

[0276] Synthesis of 3-hydroxymethyl-piperidine-1-carboxylic acid benzylester (8)

[0277] Piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (7)(1.5 g, 5.83 mmol) was dissolved in 5.8 mL of anhydrous THF, and thereaction was stirred under N₂ at −5° C. while lithium aluminum hydridedissolved in THF (7.0 mL, 11.0M) was added dropwise by addition funnelover 30 minutes. When the reaction was complete by TLC (10 min.), H₂O(0.6 mL), then 10% NaOH (1.5 mL), then H₂O (0.6 mL) were added, and thereaction was stirred for about 45 minutes. The salts were removed byfiltration and the solution was dried with sodium sulfate, filtered, andconcentrated. The crude material was purified using an ISCO CombiFlashflash column (silica, 80:20 Hexane: EtOAc to 40:60 Hexane: EtOAc) toachieve 1.24 g of pure 8 (66% yield).

Example 4

[0278] Synthesis of (3R)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester(25)

[0279] A 1.0 L round-bottom flask was charged with ester (163 mmol), THF(360 mL), MeOH (120 mL), and water (120 mL). The flask was cooled to 0°C. and a solution of LiOH (1.0 M in water, 3.25 mL; 3.25 mmol) was addedslowly dropwise. The reaction was stirred overnight at 0° C. and thenquenched with 10% HCl slowly dropwise at 0° C. until the pH˜3. Themixture was extracted with EtOAc (500 mL), washed with water (500 mL),saturated NaCl (500 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude material (40.5 g, 95% yield) was carried on withoutfurther purification.

Example 5

[0280] Synthesis of (3n)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester(26)

[0281] A 1.0 L round-bottom flask was charged with ester (49.3 g, 163mmol), THF (360 mL), MeOH (120 mL), and water (120 mL) The flask wascooled to 0° C. and a solution of LiOH (1.0 M in water; 325 mL; 325mmol) was added slowly dropwise. The reaction was stirred overnight at0° C. and then quenched with 10% HCl slowly dropwise at 0° C. until thepH 3. The mixture was extracted with EtOAc (500 mL), washed with water(500 mL), saturated NaCl (500 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude material (39.8 g, 93% yield) wascarried on without further purification.

Example 6

[0282] Synthesis of (3R)-3-Hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester (8)

[0283] A 1.0 L round-bottom flask was charged with acid (40.5 g; 154mmol) and THF (600 mL). The reaction mixture was cooled to 0° C. and a150 mL addition was charged with borane-dimethyl sulfide (10.0 M neat;46.2 mL; 462 mmol). The borane was added slowly dropwise at 0° C. andthe reaction mixture was stirred while warming to 20° C. for 2 hours.The reaction mixture was cooled to 0° C. and quenched slowly with 10%HCl until evolution of gas had ceased. The reaction mixture was stirreda further 30 minutes and then diluted with 10% NaOH (500 mL) andextracted with EtOAc (500 mL). The organic layer was washed withsaturated NaCl (500 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, hecanes/EtOAc 1:1 to 1:2) to give pure product (38.2 g, 100%yield). The enantiomeric purity was 99.16% ee as determined by chiralHPLC analysis. ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.17 (s; 2H); 4.01(m; 1H); 3.88 (bs; 1H); 3.51 (d; 2H); 3.02 (m; 1H); 2.84 (m; 1H); 1.78(m; 4H); 1.48 (m; 1H); 1.23 (m; 1H). ¹³C-NMR (300 MHz)δ(ppm) 155.7;137.1; 128.7; 128.2; 127.9; 67.2; 64.8; 53.9; 47.3; 45.0; 38.7; 27.2;24.6.

Example 7

[0284] Synthesis of (3S)-3-Hydroxymethyl-piperidine-1-carboxylic acidbenzyl ester (11)

[0285] A 1.0 L round-bottom flask was charged with acid (39.8 g, 151mmol) and THF (600 mL). The reaction mixture was cooled to 0° C. and a150 mL addition was charged with borane-dimethyl sulfide (10.0 M neat;45 mL; 450 mmol). The borane was added slowly dropwise at 0° C. and thereaction mixture was stirred while warming to 20° C. for 2 hours. Thereaction mixture was cooled to 0° C. and quenched slowly with 10% HCluntil evolution of gas had ceased. The reaction mixture was stirred afurther 30 minutes and then diluted with 10% NaOH (500 mL) and extractedwith EtOAc (500 mL). The organic layer was washed with saturated NaCl(500 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, hexanes/EtOAc1:1 to 1:2) to give pure product (36.0 g, 96% yield). The enantiomericpurity was 99.58% ee as determined by chiral HPLC analysis. ¹H-NMR (300MHz)δ(ppm) 7.40 (m; 5H); 5.14 (s; 2H); 4.01 (m; 1H); 3.86 (bs; 1H);3.50(d;2H)3.11(m;1H) 2.76(m; 1H); 1.75(m; 4H); 1.43 (m; 1H); 1.25 (m;1H).

Example 8

[0286] Synthesis of 3-formyl-piperidine-1-carboxylic acid benzyl ester(9)

[0287] To a stirring, 0° C. solution of 0.303 g (1.20 mmol) of3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (8) in CH₂Cl₂(4.0 mL) was added 0.630 g (1.44 mmol) of Dess-Martin periodinane, andthe solution was stirred under N₂. When the reaction was complete by TLC(about 30 min.), the reaction was concentrated, and then Et₂O was added.After standing for about 15 min., the reaction was filtered throughCelite wet with Et₂O, rinsed with Et₂O, and concentrated. The crudereaction was purified by column chromatography (florisil®, 100-200 mesh,2:1 Hexane: EtOAc) to achieve pure 9.

Example 9

[0288] SYNTHESIS OF (3R)-FORMYL-PIPERIDINE-1-CARBOXYLIC ACID BENZYLESTER (8)

[0289] A 500 mL RB flask was charged with DCM (300 mL) and oxalylchloride (5.8 mL; 66 mmol) and then cooled to −78° C. A 150 mL additionfunnel was charged with DMSO (8.5 mL; 120 mmol) and DCM (30 mL). TheDMSO was added slowly dropwise at −78° C. and the reaction mixture wasstirred for 30 min. The 150 mL addition funnel was charged with alcohol(16.5 g; 60 mmol) and DCM (30 mL). The alcohol was added slowly dropwiseat −78° C. and the reaction mixture was stirred for 10 min. The 150 mLaddition funnel was charged with triethyl amine (42 mL ;30 mmol). Theamine was added slowly dropwise at −78° C. and the reaction mixture wasstirred while warming to 0° C. for 30 min. The reaction mixture wasquenched with water (500 mL) and extracted with DCM (500 mL). Theorganic layer was washed with 1.0 M NaHSO₄ (500 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude material was purified byflash chromatography (florosil, hexanes/EtOAc 2:1) to give pure product(15.1 g, 100% yield). Note: The aldehyde was either used immediately inthe next step or stored at −20° C. under an argon atmosphere. ¹H-NMR(300 MHz)δ(ppm) 9.72 (s; 1H); 7.38 (m; 5H); 5.17 (s; 2H); 4.05 (m; 1H);3.79 (m; 1H); 3.41 (dd; 1H); 3.19 (m; 1H); 2.48 (m; 1H); 2.02 (m; 1H);1.73 (m; 2H); 1.58 (m; 1H).

Example 10

[0290] Synthesis of (35)-Formyl-piperidine-1-carboxylic acid benzylester (12)

[0291] A 250 mL RB flask was charged with DCM (100 mL) and oxalylchloride (2.31 mL; 26.4 mmol) and then cooled to −78° C. A 25 mLaddition funnel was charged with DMSO (3.42 mL; 48.2 mmol in 15 mL DCM).The DMSO was added slowly dropwise at −78° C. and the reaction mixturewas stirred for 30 min. The 25 mL addition funnel was charged withalcohol (6.0 g; 24.1 mmol in 15 mL DCM. The alcohol was added slowlydropwise at −78° C. and the reaction mixture was stirred for 10 min. The25 mL addition funnel was charged with triethyl amine (16.8 mL; 120mmol). The amine was added slowly dropwise at −78° C. and the reactionmixture was stirred while warming to 0° C. for 30 min. The reactionmixture was quenched with water (200 mL) and extracted with DCM (100mL). The organic layer was washed with 1.0 M NaHSO₄ (250 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (florosil, hexanes/EtOAc 2:1) to givepure product (5.53 g, 92.7% yield). The aldehyde was either usedimmediately in the next step or stored at −20° C. under an argonatmosphere. ¹H-NMR (300 MHz)δ(ppm) 9.74 (5; 1H); 7.37 (m; 5H); 5.15 (s;2H); 4.08 (m; 1H); 3.76 (m; 1H); 3.41 (dd; 1H); 3.17 (m; 1H); 2.46 (m;1H); 2.02 (m; 1H); 1.73 (m; 2H); 1.58 (m; 1H).

Example 11

[0292] Synthesis of 2-napthyl TADDOL catalyst (13)

[0293] Protocol 1

[0294] Using Schlenck glassware and air-free conditions, freshlydistilled titanium tetraisopropoxide (0.079 mL, 0.267 mmol) was added to(4R-trans)-2,2-Dimethyl-α,α,α′,α′-tetra-(2-napthyl)-1,3-dioxolane-4,5-dimethanol(0.162 g, 0.243 mmol) in anhydrous toluene freshly distilled fromsodium/benzophenone (2.21 mL), and the reaction was stirred at 40° C.for 5 hours. The reaction was then concentrated in vacuo, stored underargon until it was used without further purification.

[0295] Protocol 2

[0296] A flame dried 200 mL round-bottom flask was purged with argon andthen charged with 4R-diol (4.04 g; 6.1 mmol), toluene (60 mL; pre-driedwith 4 Å molecular sieves) and titanium (IV) isopropoxide (1.79 mL; 6.1mmol). The reaction mixture was heated to 50° C. and stirred for 4 hunder an argon atmosphere. The toluene was removed in vacuo to give thecatalyst as a pale yellow solid. The catalyst was kept under vacuum andthen used immediately after purging with argon.

[0297] Protocol 3

[0298] A flame dried 200 mL round-bottom flask was purged with argon andthen charged with 4R-diol (2.02 g; 3.0 mmol), toluene (30 mL; pre-driedwith 4 Å molecular sieves) and titanium (IV) isopropoxide (0.90 mL; 3.0mmol). The reaction mixture was heated to 50° C. and stirred for 5 hunder an argon atmosphere. The toluene was removed in vacuo to give thecatalyst as a pale yellow solid. The catalyst was kept under vacuum andthen used immediately after purging with argon.

Example 12

[0299] Synthesis of (R,S)-3-(1-Hydroxyethyl)-piperidine-1-carboxylicacid benzyl ester (15)

[0300] Protocol 1

[0301] Using Schlenck glassware and air-free conditions, anhydrous ethylether freshly distilled from sodium/benzophenone (2.43 mL) was added tocatalyst 13 prepared according to Example 11, protocol 1. Freshlydistilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added,and the reaction was cooled to −78° C. Commercial Me₂Zn (1.21 mL, 2 M intoluene) was added, and the reaction was stirred at −78° C. for 1 hour.Aldehyde 9 (0.300 g, 1.21 mmol) in Et₂O (0.3 mL) was added, and thereaction was warmed to −30° C. and stirred overnight. The reaction wasthen quenched at −30° C. with saturated aqueous NH₄Cl. Et₂O was added,and the reaction was filtered through Celite wet with Et₂O. The reactionwas dried with sodium sulfate, filtered, concentrated, and purifiedusing an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 15(0.162 g, 51%). HLPC analysis of the product presented in the Figures.¹H NMR (CDCl₃, 300 MHz) 7.43-7.31 (5H, broad s), 5.16 (2H, s), 4.30-3.60(2H, broad m), 3.63 (1H, dq, J=6.4, 6.4 Hz), 3.30-2.70 (2H, broad s),2.15-1.90 (1H, broad s), 1.84-1.72 (1H, m), 1.76-1.56 (1H, m), 1.58-1.36(2H, m), 1.23 (3H, d, J=6.4 Hz) ppm. ³C NMR (CDCl₃, 75 MHz) 155.81,137.04, 128.61, 128.08, 127.93, 68.35, 67.19, 46.61, 45.02, 43.25,27.08, 24.37, 20.95 ppm.

[0302] LRMS m/z 263.68 (M+, C₁₅H₂₁NO₃, requires 263.15.

[0303] Protocol 2

[0304] A 200 mL round-bottom flask containing 4R-TADDOL (6.12 mmol) wascharged with anhydrous ether (80 mL) and titanium isopropoxide (14.3 mL;49 mmol). The solution was cooled to −78° C. and a 2.0 M solution ofdimethyl zinc (40.5 mL; 81 mmol) was added. The solution was stirred at−78° C. for 1 h. To the solution was added aldehyde (10.0 g; 40.4 mmol)dissolved in ether (10 mL). The reaction mixture was warmed to −30° C.and stirred for 72 h. The reaction mixture was diluted with ether (500mL) and quenched by the slow addition of saturated NH₄Cl (10 mL). Theslurry was stirred at 20° C. for 10 min and then filtered throughcelite. The celite pad was washed with ether and the combined organiclayers were concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, hexanes/EtOAc 2:1 to 1:1) to givefirst, recovered 4R-ligand (3.62 g; 90% recovery) and second, pureproduct (6.51 g, 61% yield). The diastereomeric purity was 90.2% de asdetermined by achiral HPLC analysis. The enantiomeric purity of themajor diastereomer was 99.8% ee as determined by chiral HPLC analysis.¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.17 (s; 2H); 4.20 (m; 1H); 3.98(m; 2H); 3.77 (m; 1H); 3.51 (m; 1H); 3.18 (m; 1H; 2.87 (m; 1H); 1.80 (m;1H); 1.68 (m; 1H); 1.48 (m; 2H); 1.23 (d; 3H). ¹³C-NMR (300 MHz)δ(ppm)155.8; 137.2; 128.7; 128.1; 128.0; 68.8; 67.2; 46.8; 45.0; 43.5; 27.2;24.8; 21.1.

Example 13

[0305] Synthesis of(3R)-3-((1S)-1-Hydroxy-ethyl)-piperidine-1-carboxylic acid benzyl ester(15) using catalyst (13) obtained from recycled diol ligand.

[0306] The 4R-Ligand recovered from the column chromatography can beused again without any loss in yield (75% yield) or diastereoselectivity(90.3% d.e.) of 15.

Example 14

[0307] Synthesis of(3n)-3-((1S)-1-Hydroxy-ethyl)-piperidine-1-carboxylic acid benzyl ester(27)

[0308] A 200 mL round-bottom flask containing 4R-TADDOL (3.0 mmol) wascharged with anhydrous ether (40 mL) and titanium isopropoxide (7.16 mL;24.5 mmol). The solution was cooled to −78° C. and a 2.0 M solution ofdimethyl zinc (20.2 mL; 40.5 mmol) was added. The solution was stirredat −78° C. for 1 h. To the solution was added aldehyde (5.0 g; 20.2mmol) dissolved in ether (2.5 mL). The reaction mixture was warmed to−30° C. and stirred for 72 h. The reaction mixture was diluted withether (250 mL) and quenched by the slow addition of saturated NH₄Cl (5mL). The slurry was stirred at 20° C. for 10 min and then filteredthrough celite. The celite pad was washed with ether and the combinedorganic layers were concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 2:1 to 1:1)pure product (3.15 g, 59% yield). The diastereomeric purity was 89.22%de as determined by achiral HPLC analysis. The enantiomeric purity ofthe major diastereomer was >98.9% ee as determined by chiral HPLCanalysis. ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.17 (s; 2H); 4.10 (m;2H); 3.66 (m; 1H); 2.82 (m; 1H); 2.76 (m; 1H); 1.98 (m; 2H); 1.75 (m;1H); 1.48 (m; 2H); 1.30 (m; 1H); 1.22 (d; 3H). ¹³C-NMR (300 MHz)δ(ppm)155.7; 137.1; 128.7; 128.2; 128.0; 69.4; 67.3; 47.1; 44.9; 43.3; 25.8;24.9; 21.1.

Example 15

[0309] Synthesis of 2-napthyl TADDOL catalyst (14)

[0310] Using Schlenck glassware and air-free conditions, freshlydistilled titanium tetraisopropoxide (0.079 mL, 0.267 mmol) was added to(4S-trans)-2,2-Dimethyl-α,α,α′,α′-tetra-(2-napthyl)-1,3-dioxolane-4,5-dimethanol(0.162 g, 0.243 mmol) in anhydrous toluene freshly distilled fromsodium/benzophenone (2.21 mL), and the reaction was stirred at 40° C.for 5 hours. The reaction was then concentrated in vaciio, stored underargon until it was used without further purification.

[0311] A flame dried 200 mL round-bottom flask was purged with argon andthen charged with 4S-diol (4.04 g; 6.1 mmol), toluene (60 mL; pre-driedwith 4 Å molecular sieves) and titanium (IV) isopropoxide (1.79 mL; 6.1mmol). The reaction mixture was heated to 50° C. and stirred for 4 hunder an argon atmosphere. The toluene was removed in vacuo to give thecatalyst as a pale yellow solid. The catalyst was kept under vacuum andthen used immediately after purging with argon.

[0312] A flame dried 200 mL round-bottom flask was purged with argon andthen charged with 4S-diol (2.02 g; 3.0 mmol), toluene (30 mL; pre-driedwith 4 Å molecular sieves) and titanium (IV) isopropoxide (0.90 mL; 3.0mmol). The reaction mixture was heated to 50° C. and stirred for 5 hunder an argon atmosphere. The toluene was removed ilz vacuo to give thecatalyst as a pale yellow solid. The catalyst was kept under vacuum andthen used immediately after purging with argon.

Example 16

[0313] Synthesis of (R,R)-3-(1-Hydroxyethyl)-piperidine-1-carboxylicacid benzyl ester (16)

[0314] Using Schlenck glassware and air-free conditions, anhydrous ethylether freshly distilled from sodium/benzophenone (2.43 mL) was added tocatalyst 14 prepared according to Example 15, protocol 1. Freshlydistilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added,and the reaction was cooled to −78° C. Commercial Me₂Zn (1.21 mL, 2 M intoluene) was added, and the reaction was stirred at −78° C. for 1 hour.Aldehyde 9 (0.300 g, 1.21 mmol) in Et₂O (0.3 mL) was added, and thereaction was warmed to −30° C. and stirred overnight. The reaction wasthen quenched at −30° C. with saturated aqueous NH₄Cl. Et₂O was added,and the reaction was filtered through Celite wet with Et₂O. The reactionwas dried with sodium sulfate, filtered, concentrated, and purifiedusing an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 16(0.167 g, 52%). HLPC analysis of the product is depicted in the Figures.¹H NMR (CDCl₃, 300 MHz) 7.42-7.30 (5H, broad s), 5.15 (2H, s), 4.08 (2H,broad d, J=12.8 Hz), 3.67 (1H, dq, J=6.2, 6.2 Hz), 2.81 (1H, td, J=12.4,3.1 Hz), 3.90-2.60 (1H, broad), 2.40-1.90 (2H, broad), 1.80-1.68 (1H,m), 1.56-1.40 (2H, m), 1.23 (3H, d, J=6.3 Hz) ppm. ¹³C NMR (CDCl₃, 75MHz) 155.58, 137.06, 128.61, 128.07, 127.91, 69.38, 67.14, 46.94, 44.81,43.14, 25.71, 24.95, 21.03 ppm.

[0315] A 200 mL round-bottom flask containing 4S-TADDOL (14) (6.12 mmol)was charged witlLanhydrher (80 mL) and titanium isopropoxide (14.3 mL;49 mmol). The solution was cooled to −78° C. and a 2.0 M solution ofdimethyl zinc (40.5 mL; 81 mmol) was added. The solution was stirred at−78° C. for 1 h. To the solution was added aldehyde (10.6 g; 42.5 mmol)dissolved in ether (10 mL). The reaction mixture was warmed to −30° C.and stirred for 72 h. The reaction mixture was diluted with ether (500mL) and quenched by the slow addition of saturated NH4Cl (10 mL). Theslurry was stirred at 20° C. for 10 min and then filtered throughcelite. The celite pad was washed with ether and the combined organiclayers were concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, hexanes/EtOAc 2:1 to 1:1) to give pureproduct (6.95 g, 62% yield). The diastereomeric purity was 90.1% de asdetermined by achiral HPLC analysis. The enantiomeric purity of themajor diastereomer was >99.0% ee as determined by chiral HPLC analysis.¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.17 (s; 2H); 4.06 (m; 2H); 3.65(m; 1H); 2.81 (m; 1H); 2.76 (m; 1H); 1.98 (m; 2H); 1.75 (m; 1H); 1.48(m; 2H); 1.30 (m; 1H); 1.21 (d; 3H). ¹³C-NMR (300 MHz)δ(ppm) 155.7;137.1; 128.7; 128.2; 128.0; 69.2; 67.3; 47.1; 44.9; 43.3; 25.9; 25.2;21.0.

Example 17

[0316] Synthesis of (3tg-3-((1R)-1-Hydroxy-ethyl)-piperidine-1-carboxylic acid benzyl ester(28)

[0317] A 200 mL round-bottom flask containing 4S-TADDOL (14, 3.0 mmol)was charged with anhydrous ether (40 mL) and titanium isopropoxide (7.16mL; 24.5 mmol). The solution was cooled to −78° C. and a 2.0 M solutionof dimethyl zinc (20.2 mL; 40.5 mmol) was added. The solution wasstirred at −78° C. for 1 h. To the solution was added aldehyde (5.0 g;20.2 mmol) dissolved in ether (2.5 mL). The reaction mixture was warmedto −30° C. and stirred for 72 h. The reaction mixture was diluted withether (250 mL) and quenched by the slow addition of saturated NH₄Cl (5mL). The slurry was stirred at 20° C. for 10 min and then filteredthrough celite. The celite pad was washed with ether and the combinedorganic layers were concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 2:1-1:1) togive pure product (3.6 g, 67% yield). The diastereomeric purity was94.9% de as deterimined by achiral HPLC analysis. The enantiomericpurity of the major diastereomer was >99.0% ee as determined by chiralHPLC analysis. ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.14(s; 2H); 4.17(m; 1H); 3.99 (m; 2H); 3.77 (m; 1H); 3.58 (m; 1H); 3.18 (m; 1H; 2.87 (m;1H); 1.80 (m; 1H); 1.65 (m; 1H); 1.48 (m; 2H); 1.23 (d; 3H). ¹³C-NMR(300 MHz)δ(ppm) 155.9; 137.2; 128.7; 128.2; 128.0; 68.4; 67.3; 46.7;45.1; 43.3; 27.2; 24.5; 21.1.

Example 18

[0318] The chromatographic conditions used to separate the four isomers,15, 16, 27 and 28, are described below. The chromatographic conditionsgenerated the chromatographic separation depicted in FIG. 11.

[0319] Column: Chiralpak AD, 5 um, 4.6×250 mm

[0320] Mobile Phase: Hexane/IPA (97:3)

[0321] Flow Rate: 1.5 mL/min

[0322] Detection: UV 210 nm

[0323] Temperature: 5° C.

[0324] Identification of each peak was determined using authenticsamples of each stereoisomer of3-(1-hydroxyethyl)piperidine-1-carboxylic acid benzyl ester. This chiralHPLC method was subsequently used to analyze several samples ofindividual isomers. Representative chromatograms for each of the samplesare presented in FIGS. 12-15.

[0325] Using peak area normalization to quantify the amount ofindividual isomers in each sample, the following data were obtained. %(R,R)- % (S,S)- % (R,S)- % (S,R)- % de % ee Isomer Isomer Isomer Isomermajor major Sample 16 27 15 28 isomer isomer Example 12  1.23  3.0295.65 0.11 91.3  99.8 (Protocol 2) Example 14 <0.5%, ND 94.61  1.13 4.2689.2 >98.9 Example 16 96.17 <0.5%, ND  2.30 1.53 92.3 >99.0 (Protocol 2)Example 17  1.22  1.28 <0.5%, ND 97.50  95.0 >99.0

[0326] Since there was insufficient sample available to perform a spikedrecovery study, the detection limit for the minor isomers in thepresence of the major isomer was estimated at approximately 0.5%. In thecase of Example 12, (R,S)-Isomer, there was a trace of the minor(S,R)-Isomer observed in the sample, and the integration determined itto be 0.11%.

Example 19

[0327] Non-selective synthesis of a mixture of 15 and 16

[0328] MeMgI (0.80 mL, 3.0M in Et₂O) was added dropwise to a stirring,-78° C. solution of aldehyde 9 (0.313 g, 1.20 mmol) in THF (6.0 mL).When the reaction was complete by TLC, the reaction was quenched withaqueous NH₄Cl, washed with H₂O, and extracted with EtOAc. The crudereaction mixture was dried with sodium sulfate and purified using anISCO CombiFlash column (silica, 2:1 Hexane:EtOAc). HPLC analysis of theproduct is depicted in the Figures.

Example 20

[0329] Testing reaction conditions for the conversion of 9 to 15catalyzed by catalyst 13 Using Schlenck glassware and air-freeconditions, ethyl ether (2.12 mL) was added to catalyst 13. Catalyst 13had been prepared either from toluene freshly distilled fromsodium/benzophenone under argon, or it had been prepared from anhydroustoluene purchased from Aldrich and pre-dried for 24 hours with 4 Åmolecular sieves that had been heated in a vacuum oven for 24 hoursprior to their use. The amount of catalyst 13 was 5 mol %, 10 mol %, or20 mol %. The ether solvent was either freshly distilled fromsodium/benzophenone under argon, or was anhydrous ether purchased fromAldrich and pre-dried for 24 hours with 4 Å molecular sieves that hadbeen heated in a vacuum oven for 24 hours prior to their use. Titaniumtetraisopropoxide (0.347 mL, 1.27 mmol) was added, and the reaction wascooled to −78° C. Commercial Me₂Zn (1.06 mL, 2 M in toluene) was added,and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.262 g,1.06 mmol) in Et₂O (0.2 mL) was added, and the reaction was warmed to−30° C. and stirred overnight. The reaction was then quenched at −30° C.with saturated aqueous NH₄Cl. Et₂O was added, and the reaction wasfiltered through Celite wet with Et₂O. The reaction was dried withsodium sulfate, filtered, concentrated, and purified using an ISCOCombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 15. HLPC analysisof the results of these reactions is depicted in the Figures.

Example 21

[0330] Synthesis of 3-(1-phenylaminoethyl)piperidine-1-carboxylic acidtert-butyl ester 22

[0331] To a stirred suspension of3-(1-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester 21 (31mg, 0.135 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.5 mLof CH₂Cl₂-was added methanesulfonyl chloride (15.7 μL, 1.5 eq.). Themixture was stirred at room temperature for 60 min. After removal ofsolvent, aniline (50 JL) was introduced. The mixture was heated at 95°C. overnight. The crude product was purified by a preparative thin layerchromatography (EtOAc/Hexane, 1:2) to afford3-(1-phenylaminoethyl)piperidine-1-carboxylic acid tert-butyl ester 22(21 mg, 51%).

Example 22

[0332] Synthesis of(3R)-3-((1S)-1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acidbenzyl ester

[0333] A 200 mL round-bottom flask was charged with alcohol (7.19 g;27.3 mmol), DCM (100 mL) and diisopropylethylamine (5.23 mL; 30.0 mmol).The flask was cooled to 0° C. and methanesulfonyl chloride (2.32 mL;30.0 mmol) was added dropwise. The reaction was warmed to 20° C. andstirred for 2 h. The reaction mixture was diluted with DCM (150 mL). Theorganic layer was washed with saturated NaHCO₃ (250 mL), saturated NaCl(250 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, hexanes/EtOAc4:1 to 2:1 with 2% 2.0 M NH3 in EtOH) to give pure product (8.76 g, 94%yield). ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.17 (s; 2H); 4.71 (m; 1H);4.25 (m; 1H); 4.08 (m; 1H); 3.02 (m; 2H); 2;89 (bs: 3H); 2.76 (m; 1H);1.85 (m; 1H); 1.78 (m; 2H); 1.48 (d; 3H); 1.21 (m; 1H). ¹³C-NMR (300MHz)δ(ppm) 155.5; 137.0; 128.8; 128.2; 128.0; 81.0; 67.3; 45.8; 44.6;41.4; 38.8; 27.0; 24.8; 19.2.

Example 23

[0334] Synthesis of(3R)-3-((1R)-1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acidbenzyl ester (30)

[0335] A 200 mL round-bottom flask was charged with alcohol (3.15 g;12.0 mmol), DCM (100 mL) and diisopropylethylamine (2.29 mL; 13.2 mmol).The flask was cooled to 0° C. and methanesulfonyl chloride (1.02 mL;13.2 mmol) was added dropwise. The reaction was warmed to 20° C. andstirred for 2 h. The reaction mixture was diluted with DCM (150 mL). Theorganic layer was washed with saturated NaHCO₃ (250 mL), saturated NaCl(250 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, hexanes/EtOAc4:1 to 2:1 with 2% 2.0 M NH3 in EtOH) to give pure product (3.92 g, 96%yield). ¹H-NMR (300 MHz)δ(ppm) 7.40 (m; 5H); 5.19 (s; 2H); 4.75 (m; 1H);4.16 (m; 2H); 3.02 (bs; 3H); 2.82 (m: 2H); 1.99 (m; 1H); 1.78 (m; 2H);1.42 (d; 3H); 1.39 (m; 2H). ¹³C-NMR (300 MHz)δ(ppm) 155.4; 137.0; 128.8;128.3; 128.0; 80.8; 67.3; 46.2; 44.7; 41.4; 39.0; 26.0, 24.7;18.9.

Example 24

[0336] Synthesis of(3S)-3-((1S)-1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acidbenzyl ester

[0337] A 200 mL round-bottom flask was charged with alcohol (0.5 g; 1.9mmol), DCM (10 mL) and diisopropylethylamine (0.4 mL; 2.09 mmol). Theflask was cooled to 0° C. and methanesulfonyl chloride (0.16 mL; 2.09mmol) was added dropwise. The reaction was warmed to 20° C. and stirredfor 2 h. The reaction mixture was diluted with DCM (15 mL). The organiclayer was washed with saturated NaHCO₃ (25 mL), saturated NaCl (25 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (silica gel, hexanes/EtOAc 4:1 to2:1 with 2% 2.0 M NH3 in EtOH) to give pure product (616 g, 95% yield).¹H-NMR (300 MHz)δ(ppm) 7.40 (m; 5H); 5.19 (s; 2H); 4.75 (m; 1H); 4.16(mn; 2H); 3.02 (bs; 3H); 2.82 (mn: 2H); 1.99 (m; 1H); 1.78 (m; 2H); 1.42(d; 3H); 1.39 (m; 2H). ¹³C-NMR (300 MHz)δ(ppm) 155.3; 137.1; 128.7;128.2; 128.0; 80.7; 67.2; 46.2; 44.7; 41.4; 38.8; 25.9; 24.6; 18.8.

Example 25

[0338] Synthesis of(3S)-3-((1R)-1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acidbenzyl ester (32)

[0339] A 200 mL round-bottom flask was charged with alcohol (0.5 g; 1.9mmol), DCM (10 mL) and diisopropylethylamine (0.4 mL; 2.09 mmol). Theflask was cooled to 0° C. and methanesulfonyl chloride (0.16 mL; 2.09mmol) was added dropwise. The reaction was warmed to 20° C. and stirredfor 2 h. The reaction mixture was diluted with DCM (15 mL). The organiclayer was washed with saturated NaHCO₃ (25 mL), saturated NaCl (25 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (silica gel, hexanes/EtOAc 4:1 to2:1 with 2% 2.0 M NH3 in EtOH) to give pure product (0.596 g, 92%yield). ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 5.17 (s; 2H); 4.71 (m; 1H);4.25 (m; 1H); 4.08 (m; 1H); 3.02 (m; 2H); 2;89 (bs: 3H); 2.76 (m; 1H);1.85 (m; 1H); 1.78 (m; 2H); 1.48 (d; 3H); 1.21 (m; 1H). ¹³C-NMR (300MHz)δ(ppm) 155.5; 137.0; 128.8; 128.2; 128.0; 81.0; 67.3; 45.8; 44.6;41.4; 38.8; 27.0; 24.8; 19.2.

Example 26

[0340] Synthesis of(3R)-3-((1R)-1-Phenylamino-ethyl)-piperidine-1-carboxylic acid benzylester (17)

[0341] A 100 mL par-shaker flask was charged with mesylate (6.95 g, 20.4mmol) and aniline (55 mL; 611 mmol). The reaction mixture was sealed andheated to 95° C. for 48 h. The excess aniline was removed by vacuumdistillation and the crude material was purified by flash chromatography(silica gel, hexanes/EtOAc 19:1 to 4:1 with 2% 2.0 M NH3 in EtOH) togive product (7.52 g, >100% yield). The crude product was contaminatedby aniline that could not be completely removed by additional columnchromatography. The diastereomeric purity was 90.6% de as determined byHPLC analysis. ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H); 7.20 (t; 2H); 6.77(t; 1H); 6.61 (d; 2H); 5.17 (s; 2H): 4.15 (m; 2H); 3.40 (m; 2H); 2.85(m; 2H); 2.00 (m; 1H); 1.88 (m; 1H); 1.63 (m; 1H); 1.50 (m; 1H); 1.30(m; 1H); 1.21 (d; 3H). ¹³C-NMR (300 MHz)δ(ppm) 155.7; 148.0; 137.3;129.7; 128.8; 128.3; 128.1; 117.3; 113.4; 67.3; 51.1; 47.4; 45.0; 42.1;27.5; 25.4; 18.5.

Example 27

[0342] Synthesis of(3R)-3-((1S)-1-Phenylamino-ethyl)-piperidine-1-carboxylic acid benzylester (19)

[0343] A 100 mL par-shaker flask was charged with mesylate (3.92 g, 11.5mmol) and aniline (31 mL; 344 mmol). The reaction mixture was sealed andheated to 95° C. for 48 h. The excess aniline was removed by vacuumdistillation and the crude material was purified by flash chromatography(silica gel, hexanes/EtOAc 19:1 to 4:1 with 2% 2.0 M NH3 in EtOH) togive product (4.09 g, >100% crude yield). The crude product wascontaminated by aniline that could not be completely removed byadditional column chromatography. ¹H-NMR (300 MHz) 6 (ppm) 7.38 (m; 5H);7.20 (t; 2H); 6.77 (t; 2H); 6.61 (d; 1H); 5.17 (s; 2H): 4.40 (m; 1H);4.18 (m; 1H); 3.39 (m; 1H); 2.80 (m; 2H); 2.58 (m; 1H); 1.92 (m; 1H);1.78 (m; 1H); 1.53 (m; 2H); 1.28 (m; 1H); 1.19 (d; 3H). ¹³C-NMR (300MHz)δ(ppm) 155.7; 148.0; 137.4; 129.8; 128.9; 128.3; 128.2; 117.4;113.6; 67.4; 51.2; 48.1; 45.1; 42.1; 27.5; 25.8; 18.3.

Example 28

[0344] Synthesis of(3S)-3-((1R)-1-Phenylamino-ethyl)-piperidine-1-carboxylic acid benzylester (33)

[0345] A 100 mL par-shaker flask was charged with mesylate (0.3 g, 0.88mmol) and aniline (5 mL; 55.5 mmol). The reaction mixture was sealed andheated to 90° C. for 48 h. The excess aniline was removed by vacuumdistillation and the crude material was purified by flash chromatography(silica gel, hexanes/EtOAc 19:1 to 4:1 with 2% 2.0 M NH3 in EtOH) togive product (0.272 g, 91% yield). The diastereomeric purity was 84.36%de as determined by HPLC analysis. ¹H-NMR (300 MHz)δ(ppm) 7.37 (m; 5H);7.20 (t; 2H); 6.70 (t; 2H); 6.61 (d; 1H); 5.15 (s,2H): 4.40(m;1H);3.40(m;1H); 2.78 (m; 2H); 2.52 (m; 1H); 1.92 (m; 1H); 1.78 (rn; 1H);1.53 (m; 2H); 1.28 (m; 1H); 1.19 (d; 3H). ¹³C-NMR (300 MHz)δ(ppm) 155.6;147.8; 137.3; 129.6; 128.9; 128.2; 128.1; 117.4; 113.5; 67.3; 51.0;48.0; 45.0; 42.1; 27.4; 25.6; 18.2.

[0346] The lower % de observed for this reaction reflects the % de ofthe starting alcohol (27), and not of a lack of stereochemical integrityfor this reaction. Alcohol 27 was synthesized from aldehyde 12 that hadbeen stored at room temperature. Storage of the aldehyde at roomtemperature results in reduced enantiopurity.

Example 29

[0347] Synthesis of(3S)-3-((Is)-1-Phenylamino-ethyl)-piperidine-1-carboxylic acid benzylester (34)

[0348] A 100 mL par-shaker flask was charged with mesylate (0.45 g, 1.32mmol) and aniline (7.5 mL; 83.25 mmol). The reaction mixture was sealedand heated to 90° C. for 48 h. The excess aniline was removed by vacuumdistillation and the crude material was purified by flash chromatography(silica gel, hexanes/EtOAc 19:1 to 4:1 with 2% 2.0 M NH3 in EtOH) togive product (0.381 g, 85% yield). The diastereomeric purity was 92.86%de as determined by HPLC analysis. ¹H-NMR (300 MHz)δ(ppm) 7.38 (m; 5H);7.20 (t; 2H); 6.77 (t; 1H); 6.61 (d; 2H); 5.17 (s; 2H): 4.15 (m; 2H);3.40 (m; 2H); 2.85 (m; 2H); 2.00 (m; 1H); 1.88 (m; 1H); 1.63 (m; 1H);1.50 (m; 1H); 1.30 (m; 1H); 1.21 (d; 3H). ¹³C-NMR (300 MHz)δ(ppm) 155.7;148.0; 137.3; 129.7; 128.8; 128.3; 128.1; 117.3; 113.4; 67.3; 51.1;47.4; 45.0; 42.1; 27.5; 25.4; 18.5.

Example 30

[0349] Synthesis of(3R)-3-((1R)-1-Phenylamino-ethyl)-piperidine-1-carboxylic acid benzylester (17)

[0350] A 50 mL round-bottom flask was charged with alcohol (1.0 g, 3.80mmol), DCM (5 mL) and 2,6-lutidine (487 μL; 4.20 mol). The reactionmixture was cooled to −78° C. and Tf₂O (703 μL ; 4.18 mmol) was addeddropwise. The reaction mixture was stirred at −78° C. for 1 h. To thereaction mixture was added aniline (519 mL; 5.70 μmol) and 2,6-lutidine(663 μL; 5.70 mmol). The reaction mixture was warmed to 0° C. andstirred for 2 h. The reaction mixture was diluted with DCM (50 mL),washed with saturated NaHCO₃ (50 mL), saturated NaCl (50 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 19:1 to 4:1with 2% 2.0 M NH3 in EtOH) to give product (720 mg, 56% yield). ¹H-NMR(300 MHz) δ(ppm) 7.38 (m; 5H); 7.20 (t; 2H); 6.77 (t; 1H); 6.61 (d; 2H);5.17 (s; 2H): 4.15 (m; 2H); 3.40 (m; 2H); 2.85 (m; 2H); 2.00 (m; 1H);1.88 (m; 1H); 1.63 (m; 1H); 1.50 (m; 1H); 1.30 (m; 1H); 1.21 (d; 3H).¹³C-NMR (300 MHz)δ(ppm) 155.7; 148.0; 137.3; 129.7; 128.8; 128.3; 128.1;117.3; 113.4; 67.3; 51.1; 47.4; 45.0; 42.1; 27.5; 25.4; 18.5.

Example 31

[0351] Synthesis of N-f1-[1-phenethylpiperidin-3-yl)ethyl]-N-Phenylpropionamide 23

[0352] To a solution of afford3-(1-phenylaminoethyl)piperidine-1-carboxylic acid tert-butyl ester 22and N,N-diisopropylethylamine (5 equiv) in CH₂Cl₂ (0.5 M) at 0° C. wasadded propionyl chloride (3.0 equiv). The reaction mixture was shakenoven-ight. The mixture was poured into 10% NaOH, then extracted withEtOAc. The extracts were combined and washed with aqueous NaHCO₃, driedover sodium sulfate, filtered, and concentrated. The crude material waspurified by column chromatography (silica gel, hexane:EtOAc, 4:1) togive N-[1-(1-phenethylpiperidin-3-yl)ethyl]-N-Phenylpropionamide 23.

Example 32

[0353] Synthesis of(3R)-3-[(1R)-1-(Phenyl-propionyl-amino)-ethyl]-piperidine-1-carboxylicacid benzyl ester (18)

[0354] A 100 mL round-bottom flask was charged with amine (obtained bySN2 displacement of the corresponding triflate) (5.45 g; 16.1 mmol), DCM(20 mL) and diisopropylethylamine (5.61 mL: 32.2 mmol). The reactionmixture was cooled to 0° C. and propionyl chloride (2.80 mL; 32.2 mmol)was added. The reaction mixture was stirred at 20° C. for 16 h. Thereaction mixture was diluted with EtOAc (1.00 mL). The organic layer waswashed with saturated NaHCO₃ (100 mL), saturated NaCl (100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 4:1 to 2:1)to give product (5.72 g, 90% yield). ¹H-NMR (300 MHz)δ(ppm) 7.40 (m;7H); 7.10 (d; 3H); 5.08 (s; 2H); 4.78 (m; 1H); 4.00 (m; 2H); 2.93 (m;1H); 2.76 (t; 1H); 2.05 (m; 1H); 1.98 (q; 2H); 1.80 (m; 2H); 1.50 (m;4H); 1.02 (m; 5H). ¹³C-NMR (300 MHz)δ(ppm) 174.2; 155.4; 139.0; 137.1;131.0; 129.7; 128.7; 128.5; 128.1; 128.0; 67.2; 52.8; 47.5; 44.7; 39.6;28.8; 28.7; 24.9; 17.3; 10.0.

Example 33

[0355] Synthesis of(3R)-3-[(1S)-1-(Phenyl-propionyl-amino)-ethyl]-piperidine-1-carboxylicacid benzyl ester (20)

[0356] A 100 mL round-bottom flask was charged with amine (obtained bySN² displacement of the corresponding mesylate) (1.37 g; 4.05 mmol), THF(25 mL), potassium bicarbonate (2.79 g mL: 20.0 mmol) and propionylchloride (1.76 mL; 20.0 mmol). The reaction mixture was heated to 50° C.and stirred for 16 h. The reaction mixture was cooled to roomtemperature and diluted with EtOAc (100 mL). The organic layer waswashed with saturated NaHCO₃ (100 mL), saturated NaCl (100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 4:1 to 2:1)to give product (2.28 g, 50% yield). ¹H-NMR (300 MHz)δ(ppm) 7.48 (d;1H); 7.40 (m; 6H); 7.10 (d; 3H); 5.18-(s; 2H); 4.78 (m; 1H); 4.44 (m;1H); 4.22 (m; 1H); 2.78 (m; 2H); 1.98 (m; 2H); 1.80 (m; 4H); 1.40 (m;2H); 1.02 (m; 5H). ¹³C-NMR (300 MHz)δ(ppm) 174.5; 155.0; 138.8; 137.1;129.5; 129.0; 128.8; 128.5; 124.0; 120.1; 67.6; 52.2; 48.6; 44.7; 40.5;30.8; 28.5; 25.5; 17.1; 10.0.

Example 34

[0357] Synthesis of(3n)-3-[(1R)-1-(Phenyl-propionyl-amino)-ethyl]-piperidine-1-carboxylicacid benzyl ester (35)

[0358] A 100 mL round-bottom flask was charged with amine (obtained bySN² displacement of the corresponding mesylate) (250 g; 0.73 mmol), DCM(5 mL) and diisopropylethylamine (0.65 mL: 3.65 mmol). The reactionmixture was cooled to 0° C. and propionyl chloride (0.20 mL; 2.28 mmol)was added. The reaction mixture was stirred at 0° C. for 4 h. Thereaction mixture was diluted with EtOAc (5 mL). The organic layer waswashed with saturated NaHCO₃ (10 mL), saturated NaCl (10 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 4:1 to 2:1)to give product (0.165 g, 57% yield). ¹H-NMR (300 MHz)δ(ppm) 7.48 (d;1H); 7.40 (m; 6H); 7.10 (d; 3H); 5.18 (s; 2H); 4.78 (m; 1H); 4.44 (m;1H); 4.22 (m; 1H); 2.78 (m; 2H); 1.98 (m; 2H); 1.80 129.5; 129.0; 128.8;128.5; 124.0; 120.1; 67.6; 52.2; 48.6; 44.7; 40.5; 30.8; 28.5; 25.5;17.1; 10.0.

Example 35

[0359] Synthesis of(3S)-3-[(1S)-1-(Phenyl-propionyl-amino)-ethyl]-piperidine-1-carboxylicacid benzyl ester (36)

[0360] A 100 mL round-bottom flask was charged with amine (obtained bySN² displacement of the corresponding mesylate) (0.300 g; 0.88 mmol),DCM (6 mL), and diisopropylethylamine (0.78 mL: 4.38 mmol). The reactionmixture was cooled to 0° C. and propionyl chloride (0.24 mL; 2.74 mmol)was added. The reaction mixture was stirred at 0° C. for 4 h. Thereaction mixture was diluted with EtOAc (6 mL). The organic layer waswashed with saturated NaHCO₃ (10 mL), saturated NaCl (10 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (silica gel, hexanes/EtOAc 4:1 to 2:1)to give product (0.236 g, 68% yield). ¹H-NMR (300 MHz)δ(ppm) 7.40 (m;7H); 7.10 (d; 3H); 5.08 (s; 2H); 4.78 (m; 1H); 4.00 (m; 2H); 2.93 (m;1H); 2.76 (m; 1H); 1.98 (q; 2H); 1.80 (m; 2H); 1.50 (m; 4H); 1.02 (m;5H). ¹³C-NMR (300 MHz)δ(ppm) 174.2; 155.4; 139.0; 137.1; 131.0; 129.7;128.7; 128.5; 128.1; 128.0; 67.2; 53.8; 52.8; 47.5; 44.7; 39.6; 28.8;28.7; 24.9; 17.3; 10.0.

Example 36

[0361] Synthesis ofN-[1-(1-phenethylpiperidine-3-yl)ethyl]-N-Phenylpropionamide 24

[0362] To a solution ofN-[1-(1-phenethylpiperidin-3-yl)ethyl]-N-Phenylpropionamide 23 inCH₂Cl₂(0.45 M)at 0° was added TFA. After stirring for30 min., thesolventand excess TFA was removed by evaporation. The residue was dissolved in1.5 mL of CH₃CN, to which K₂CO3 and (2-bromoethyl)benzene (2 equiv) wereadded. The mixture was stirred at 50° C. overnight. After cooling downto room temperature, 10% NaOH was added. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine and dried with sodium sulfate,filtered, and concentrated. The crude product was purified by flashsilica gel chromatography (5% MeOH in CH₂Cl₂) to provideN-[1-(1-phenethylpiperidine-3-yl)ethyl]-N-Phenylpropionamide 24.

Example 37

[0363] Synthesis of(3R)-3-[(1R)-1-(Phenyl-propionyl-amino)-ethyl]-piperidine (37)

[0364] A 100 mL Parr shaker-flask was charged with Cbz-protected amine(1.01 g; 2.53 mmol) and MeOH (10 mL). The flask was purged with argonand 10% (w/w) Pd/C was added (270 mg; 0.25 mmol). The reaction mixturewas fitted with a hydrogen balloon and hydrogenated at 20° C. for 16 h.The reaction mixture was filtered through celite and the celite padwashed with MeOH. The combined organics were concentrated in vicuto togive product (660 mg, 99% yield). ¹H-NMR (300 MHz)δ(ppm) 7.41 (m; 3H);7.10 (d; 2H); 4.75 (m; 1H); 3.25 (dd; 2H); 2.68 (dt; 1H); 2.51 (t; 1H);2.16 (dd; 1H); 1.95 (m; 4H); 1.80 (m; 2H); 1.40 (m; 1H); 1.02 (m; 5H).¹³C-NMR (300 MHz)δ(ppm) 174.4; 139.3; 129.8; 129.5; 128.7; 53.2; 47.6;44.8; 38.5; 28.7; 27.8; 23.2; 17.0; 9.9.

Example 38

[0365] Synthesis of(3R)-3-[(1S)-1-(Phenyl-propionyl-amino)-ethyl]-piperidine (38)

[0366] A 100 mL Parr shaker-flask was charged with Cbz-protected amine(2.28 g; 5.70 mmol) and MeOH (10 mL). The flask was purged with argonand 10% (w/w) Pd/C was added (604 mg; 0.57 mmol). The reaction mixturewas fitted with a hydrogen balloon and hydrogenated at 20° C. for 16 h.The reaction mixture was filtered through celite and the celite padwashed with MeOtf. The combined organics were concentrated in vacuo togive product (1.45 g, 98% yield). ¹H-NMR (300 MHz)δ(ppm) 7.41 (m; 3H);7.10 (d; 2H); 4.78 (m; 1H); 3.50 (d; 1H); 3.23 (d; 1H); 2.79 (t; 2H);2.00 (m; 3H); 1.80 (m; 4H); 1.23 (m; 1H); 1.02 (m; 5H). ¹³C-NMR (300MHz) 6 (ppm) 174.6; 138.7; 130.2; 129.3; 128.76; 52.4; 48.7; 45.2; 38.6;28.6; 27.2; 23.5; 16.9; 9.9.

Example 39

[0367] Synthesis ofN-[(1R)-1-((3S)-1-Phenethyl-piperidin-3-yl)-ethyl]-N-phenyl-propionamide(2)

[0368] A 25 mL round-bottom flask was charged with amine (133 mg; 0.51mmol), K₂CO₃ (218 mg; 1.5 mmol), MeCN (1 mL), H₂O (1 mL) and phenethylbromide (84 μL; 0.61 mmol). The reaction mixture was heated to 70° C.and stirred for 3 h. The reaction mixture was cooled to room temperatureand diluted with DCM (50 mL). The organic layer was washed with water(50 mL), saturated NaCl (50 mL), dried (Na₂SO4), filtered andconcentrated in vacuo. The crude material was purified chromatography(silica gel, hexanes/EtOAc 4:1 with 2% 2.0 M NH3 in EtOH) to give pureproduct (72 mg, 40% yield). ¹H-NMR (300 MHz)δ(ppm) 7.42 (m; 5H); 7.21(t; 2H); 6.78 (t; 1H); 6.60 (d; 2H); 5.17 (m, 2H); 4.40 (m; 1H); 4.19(m; 1H); 3.49 (m; 2H); 3.40 (m; 2H); 2.82 (m; 2H); 2.59 (m; 2H); 1.98(m; 1H); 1.78 (m; 1H); 1.57 (m; 2H); 1.22 (m; 2H); 1.18 (d; 3H) 1.05 (m;1H). ¹³C-NMR (300 MHz)δ(ppm) 174.3; 140.7; 139.2; 131.1; 129.8; 129.0;128.6; 126.3; 120.1; 61.2; 58.0; 54.6; 52.8; 40.4; 34.0; 28.8; 28.3;25.7; 17.4; 10.3.

Example 40

[0369] Chiral Chromatographic Purification of Stereoisomers ofN-[1-(1-phenethyl-piperidin-3-yl)- ethyl]-N-phenyl-propionamide (24)

[0370] The chromatographic conditions to separate the four (1, 2, 3, and4) possible stereoisomers of compound 24 are described below. Thechromatographic conditions generated the chromatographic separationdepicted in FIG. 40. Column: Chiralcel OD, 10 um, 4.6 × 250 mm MobilePhase: Hexane/Ethanol/Methanol/Diethylamine (98:0.5:1.5:0.1) Flow Rate:0.7 mL/min Detection: UV 220 nm Temperature: Ambient

[0371] Identification of each peak was made by comparison authenticsamples of each isomer ofN-[1-(1-phenethyl-piperidin-3-yl)-ethyl]-N-phenyl-propionamide (24).This chiral HPLC method was used to analyze 2 obtained from Example 39.See FIG. 41. Using peak area normalization to quantitate the amounts ofindividual isomers in this sample, the following results were obtainedfor the sample. % de % ee %2 %3 %1 %4 major major Sample (R,S) (S,R)(R,R) (S,S) isomer isomer Example 39 95.46 0.14 1.67 2.73 91.2% 99.7%

Example 41

[0372] Achiral (reverse-phase) HPLC analysis of 15 (See FIG. 16) FIG. 16depicts a series of HPLC analyses (at both 254 and 220 nm) of compound15 (8.42 min) alone in the first two plots, compound 15 co-injected witha mixture of compounds 15 and 16 in the 3^(rd) and 4^(th) plots, and ofa mixture of compounds 15 and 16 in the 5^(th) and 6^(th) plots. Thepeak at 8.78 min. is an impurity.

Example 42

[0373] Achiral (reverse-phase) HPLC analysis of 16 (See FIG. 17) FIG. 17depicts a series of HPLC analyses (at both 254 and 220 nm) of compound16 (8.16 min) alone in the first two plots, compound 16 co-injected witha mixture of compounds 15 and 16 in the 3^(rd) and 4^(th) plots, and ofa mixture of compounds 15 and 16 in the 5^(th) and 6th plots.

Example 43

[0374] Achiral (reverse-phase) HPLC analyses of 15 and 16 (See FIG. 18)FIG. 18 depicts a series of HPLC analyses (at both 254 and 220 nm) ofcompound 15 (8.42 min) alone in the first two plots, compound 15co-injected with compound 16 in the 3^(rd) and 4^(th) plots, andcompound 16 in the 5^(th) and 6th plots.

Example 44

[0375] Achiral (reverse-phase) HPLC analyses of 15 under a variety ofreaction conditions (See Figure FIG. 19 depicts a series of HPLCanalyses (at 254 nm) of compound 15 (8.8 min) obtained from a variety ofexperiments run simultaneously and with differing conditions for eachreaction. The first two plots are with 20 mol % of catalyst 13. Thefirst reaction used solvents distilled from sodium/benzophenone underargon, and the second used solvents purchased anhydrous from Aldrich anddried with activated 4 Å molecular sieves. The 3^(rd) and 4^(th) plotsare with 10 mol % of catalyst 13. The 3^(rd) reaction used solventdistilled from sodium/benzophenone under argon, and the -4 ^(th),experiment used anhydrous solvents pre-dried with activated 4 Åmolecular sieves. The 5th and 6^(th) plots are for experiments whichused 5 mol % of catalyst 13. The 5^(th) reaction used solvent distilledfrom sodium/benzophenone under argon, and the 6^(th) experiment usedanhydrous solvents pre-dried with activated 4 Å molecular sieves. The7^(th) plot is a co-injection of compound 15 obtained from the firstreaction (plot 1) with 16 (8.3 min).

Example 45

[0376] Opiate receptor binding of certain enantiomerically pure3-substituted piperidines (IC₅₀s) The opioid (μ, κ,δ) receptor-bindingcapabilities of compounds prepared using the methods of the presentinvention were determined according to the procedures outlined by Wanget al. (FEBS Letters 1994, 338, 217), Maguire et al. (Eur. J. Pharmacol.1992, 213, 219), and Simonin et al. (Mol. Pharmacol. 1994, 46, 1015).Certain results from these assays are tabulated below.

μ κ δ Compound (μM) (μM) (μM) 1 <1 <1 <10 2 <1 <5 >10 3 <1 <5 >10 4 <1<1 >10

[0377] Incorporation by Reference the pa tents and publications citedherein are hereby incorporated by reference.

[0378] Equivalents

[0379] skilled in the art will recognize, or be able to ascertain usingno more than routine on, many equivalents to the specific embodiments ofthe invention described equivalents are intended to be encompassed bythe following claims.

We claim:
 1. A compound of formula I:

wherein n is 0, 1, or 2; R is H, aralkyl, or —CO₂R′; R′ is alkyl, aryl,or aralkyl; Z is NHR″ or OH; and R″ is H, alkyl, aryl, or aralkyl. 2.The compound of claim 1, wherein n is
 1. 3. The compound of claim 1,wherein R is Cbz.
 4. The compound of claim 1, wherein R is —CH₂CH₂Ph. 5.The compound of claim 1, wherein R is H.
 6. The compound of claim 1,wherein R′ is methyl.
 7. The compound of claim 1, wherein Z is OH. 8.The compound of claim 1, wherein Z is NHR″; and R″ is phenyl.
 9. Thecompound of claim 1, wherein n is 1; and R is Cbz.
 10. The compound ofclaim 1, wherein n is 1; and R′ is Me.
 11. The compound of claim 1,wherein n is 1; R′ is Me; and Z is OH.
 12. The compound of claim 1,wherein n is 1; R′ is Me; Z is OH; and R is Cbz.
 13. The compound ofclaim 1, wherein n is 1; R′ is Me; Z is NHR″; and R″ is phenyl.
 14. Thecompound of claim 1, wherein n is 1; R′ is Me; Z is NHR″; R″ is phenyl;and R is Cbz.
 15. The compound of claim 1, wherein n is 1; R is Cbz; andR′ is methyl.
 16. The compound of claim 1, wherein n is 1; and R is—CH₂CH₂Ph.
 17. The compound of claim 1, werein n is 1; R is —CH₂CH₂Ph;and R′ methyl.
 18. The compound of claim 1, wherein n is 1; R is—CH₂CH₂Ph; R′ is methyl; and Z is OH.
 19. The compound of claim 1,wherein n is 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ isphenyl.
 20. A compound of formula II:

n is 0, 1, or 2; R is H, aralkyl, or —CO₂R′; R′ is alkyl, aryl, oraralkyl; Z is NHR″ or OH,and R″ is H, alkyl, aryl, or aralkyl.
 21. Thecompound of claim 20, wherein n is
 1. 22. The compound of claim 20,wherein R is Cbz.
 23. The compound of claim 20, wherein R is —CH₂CH₂Ph.24. The compound of claim 20, wherein R is H.
 25. The compound of claim20, wherein R′ is methyl.
 26. The compound of claim 20, wherein Z is OH.27. The compound of claim 20, wherein Z is NHR″; and R″ is phenyl. 28.The compound of claim 20, wherein n is 1; and R is Cbz.
 29. The compoundof claim 20, wherein n is 1; and R′ is Me.
 30. The compound of claim 20,wherein n is 1; R′ is Me; and Z is OH.
 31. The compoundof claim 20,wherein-n is 1; R′ is Me; and Z is OH; and R″ is bz.
 32. The compound ofclaim 20, wherein n is 1; R′ is Me; Z is NHR″; and R″ is phenyl.
 33. Thecompound of claim 20, wherein n is 1; R′ is Me; Z is NHR″; R″ is phenyl;and R is Cbz.
 34. The compound of claim 20, wherein n is 1; R is Cbz;and R′ is methyl.
 35. The compound of claim 20, wherein n is 1; and R is—CH₂CH₂Ph.
 36. The compound of claim 20, wherein n is 1; R is —CH₂CH₂Ph;and R′ is methyl.
 37. The compound of claim 20, wherein n is 1; R is—CH₂CH₂Ph; R′ is methyl; and Z is OH.
 38. The compound of claim 20,wherein n is 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ isphenyl.
 39. A compound of formula III:

n is 0, 1, or 2; R is H, aralkyl, or —CO₂R′; R′ is alkyl, aryl, oraralkyl; Z is NHR″ or OH; and R″ is H, alkyl, aryl, or aralkyl.
 40. Thecompound of claim 39, wherein n is
 1. 41. The compound of claim 39,wherein R is Cbz.
 42. The compound of claim 39, wherein R is —CH₂CH₂Ph.43. The compound of claim 39, wherein R is H.
 44. Theorompound of claim39, wherein R′ is methyl.
 45. The compound of claim 39, wherein Z is OH.46. The compound of claim 39, wherein Z is NHR″; and R″ is phenyl. 47.The compound of claim 39, wherein n is 1; and R is Cbz.
 48. The compoundof claim 39, wherein n is 1; and R′ is Me.
 49. The compound of claim 39,wherein n is 1; R′ is Me; and Z is OH.
 50. The compound of claim 39,wherein n is 1; R′ is Me; Z is OH; and R is Cbz.
 51. The compound ofclaim 39, wherein n is 1; R′ is Me; Z is NHR″; and R″ is phenyl.
 52. Thecompound of claim 39, wherein n is 1; R′ is Me; Z is NHR″; R″ is phenyl;and R is Cbz.
 53. The compound of claim 39, wherein n is 1; R is Cbz;and R′ is methyl.
 54. The compound of claim 39, wherein n is 1; and R is—CH₂CH₂Ph.
 55. The compound of claim 39, wherein n is 1; R is —CH₂CH₂Ph;and R′ is methyl.
 56. The compound of claim 39, wherein n is 1; R is—CH₂CH₂Ph; R′ is methyl; and Z is OH.
 57. The compound of claim 39,wherein n is 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ isphenyl.
 58. A compound of formula IV:

n is 0,1, or 2; R is H, aralkyl, or —CO₂R′; R′ is alkyl, aryl, oraralkyl; Z is NHR″ or OH; and R″ is H, alkyl, aryl, or aralkyl.
 59. Thecompound of claim 58, wherein n is
 1. 60. The compound of claim 58,wherein R is Cbz.
 61. The compound of claim 58, wherein R is —CH₂CH₂Ph.62. The compound of claim 58, wherein R is H.
 63. The compound of claim58, wherein R′ is methyl.
 64. The compound of claim 58, wherein Z is OH.65. The compound of claim 58, wherein Z is NHR″; and R″ is phenyl. 66.The compound of claim 58, wherein n is 1; and R is Cbz.
 67. The compoundof claim 58, wherein n is 1; and R′ is Me.
 68. The compound of claim 58,wherein n is 1; R′ is Me; and Z is OH.
 69. The compound of claim 58,wherein n is 1; R′ is Me; Z is OH; and R is Cbz.
 70. The compound ofclaim 58, wherein n is 1; R′ is Me; Z is NHR″; and R″ is phenyl.
 71. Thecompound of claim 58, wherein n is 1; R′ is Me; Z is NHR″; R″ is phenyl;and R is Cbz.
 72. The compound of claim 58, wherein n is 1; R is Cbz;and R′ is methyl.
 73. The compound of claim 58, wherein n is 1; and R is—CH₂CH₂Ph.
 74. The compound of claim 58, wherein n is 1; R is —CH₂CH₂Ph;and R′ is methyl.
 75. The compound of claim 58, wherein n is 1; R is—CH₂CH₂Ph; R′ is methyl; and Z is OH.
 76. The compound of claim 58,wherein n is 1; R is —CH₂CH₂Ph; R′ is methyl; Z is NHR″; and R″ isphenyl.
 77. A method of preparing an enantiomerically enriched3-(1-hydroxyalkyl)-substituted cyclic amine, comprising the step ofadding stereoselectively a nucleophilic alkyl or aryl to substantiallyone enantiomer of a 3-substituted cyclic amine, wherein the3-substituent contains a carbonyl group, with a chiral transition metalcomplex and a metal alkyl or metal aryl to form said3-(1-hydroxyalkyl)-substituted cyclic amine.
 78. The method of claim 77,wherein said cyclic amine is a pyrrolidine.
 79. The method of claim 77,wherein said cyclic amine is a piperidine.
 80. The method of claim 77,wherein said cyclic amine is an azepine.
 81. The method of claim 77,wherein said chiral transition metal complex is a TADDOL catalyst; andsaid metal alkyl is a zinc alkyl.
 82. The method of claim 81, whereinsaid zinc alkyl is Me₂Zn.
 83. The method of claim 77, wherein saidchiral transition metal complex is a TADDOL catalyst; and said metalaryl is a zinc aryl.
 84. The method of claim 83, wherein said zinc arylis Ph₂Zn.
 85. The method of claim 77, wherein said substantially oneenantiomer of a 3-substituted cyclic amine has an R configuration; andsaid step of a stereochemical nucleophilic addition produces a chiralcarbon having an R configuration.
 86. The method of claim 77, whereinsaid substantially one enantiomer of a 3-substituted cyclic amine has anR configuration; and said step of a stereochemical nucleophilic additionproduces a chiral carbon having an S configuration.
 87. The method ofclaim 77, wherein said substantially one enantiomer of a 3-substitutedcyclic amine has an S configuration; and said step of a stereochemicalnucleophilic addition produces a chiral carbon having an Sconfiguration.
 88. The method of claim 77, wherein said substantiallyone enantiomer of a 3-substituted cyclic amine has an S configuration;and said step of a stereochemical nucleophilic addition produces achiral carbon having an R configuration.
 89. The method of claim 81 or83, wherein said TADDOL catalyst comprises 2-napthyl substitution. 90.The method of claim 77 wherein said substantially one enantiomer of a3-formyl-cyclic amine is prepared by a method comprising the followingsteps: protecting the nitrogen atom of substantially one enantiomer of a3-ester substituted cyclic amine with a protecting group; reducing saidester to form an alcohol; and oxidizing said alcohol to an aldehyde. 91.The method of claim 90, wherein said cyclic amine is a pyrrolidine. 92.The method of claim 90, wherein said cyclic amine is a piperidine. 93.The method of claim 90, wherein said cyclic amine is an azepine.
 94. Themethod of claim 90, wherein said protecting group is selected from thegroup consisting of Cbz and BOC.
 95. The method of claim 90, whereinreducing said ester is carried out in one step with LAH.
 96. The methodof claim 90, wherein reducing said ester is carried out in two steps,wherein the first step converts said ester to an acid; and the secondstep converts said acid to an alcohol.
 97. The method of claim 96,wherein said second step is carried out with BH₃-Me₂S.
 98. The method ofclaim 90 or 92, further comprising the steps of: reacting said3-(1-hydroxyalkyl)-substituted cyclic amine with a sulfonyl halide orsulfonyl anhydride to produce a 3-(1-sulfonyloxyalkyl)-substitutedcyclic amine; reacting said 3-(1-sulfonyloxyalkyl)-substituted cyclicamine with an aryl amine or an aryl alcohol to give by a nucleophilicsubstitution reaction a 3-(1-arylaminoalkyl)-substituted cyclic amine ora 3-(1-aryloxyalkyl)-substituted cyclic amine.
 99. The method of claim98, further comprising the step of converting said amine to an amide.100. The method of claim 99, further comprising the step of deprotectingthe ring nitrogen of said cyclic amine.
 101. The method of claim 100,further comprising the step of alkylating or aralkylating the ringnitrogen of said cyclic amine.
 102. The method of claim 81 or 83,wherein about 5 mol % to about 20 mol % TADDOL catalyst is used. 103.The method of claim 81 or 83, wherein about 10 mol % to about 15 mol %TADDOL catalyst is used.
 104. The method of claim 81 or 83, whereinabout 15 mol % TADDOL catalyst is used.